中国科学院微生物研究所、中国微生物学会主办
文章信息
- 潘剑锋, 尚方正, 马荣, 王敏, 戎友俊, 梁丽丽, 牛舒冉, 李彦伯, 齐云鹏, 张燕军, 李金泉
- PAN Jianfeng, SHANG Fangzheng, MA Rong, WANG Min, RONG Youjun, LIANG Lili, NIU Shuran, LI Yanbo, QI Yunpeng, ZHANG Yanjun, LI Jinquan
- 长非编码RNA编码微肽的研究进展
- Advances of long non-coding RNA encoded micro-peptides
- 生物工程学报, 2022, 38(9): 3194-3214
- Chinese Journal of Biotechnology, 2022, 38(9): 3194-3214
- 10.13345/j.cjb.210916
-
文章历史
- Received: December 9, 2021
- Accepted: March 29, 2022
- Published: July 20, 2022
2. 农业部肉羊遗传育种重点实验室, 内蒙古 呼和浩特 010018;
3. 内蒙古自治区动物遗传育种与繁殖重点实验室, 内蒙古 呼和浩特 010018;
4. 内蒙古自治区山羊遗传育种工程技术研究中心, 内蒙古 呼和浩特 010018
2. Key Laboratory of Meat Sheep Genetics and Breeding, Ministry of Agriculture, Hohhot 010018, Inner Mongolia Autonomous Region, China;
3. Key Laboratory of Animal Genetics, Breeding and Reproduction in Inner Mongolia, Hohhot 010018, Inner Mongolia Autonomous Region, China;
4. Goat Genetics and Breeding in Inner Mongolia Autonomous Region Engineering Technology Research left Hohhot 010018, Inner Mongolia Autonomous Region, China
人类基因组有3/4能够被转录,但只有约2%的基因具有编码蛋白质的能力[1]。DNA元件百科全书(encyclopedia of DNA elements, ENCODE) 的数据表明,在编码蛋白质基因外的转录物中,含有大量的非编码RNA (non-coding RNA, ncRNA)[2]。近年的研究发现,这些ncRNA中可能含有一个或多个短开放阅读框(short open reading frames, sORF),并且可能编码一种小于100个氨基酸的微小蛋白质(肽),称为微肽(micro-peptide)[3-4]。长非编码RNA (long non-coding RNA, lncRNA) 是ncRNA的一个亚类,其长度超过200 nt,由RNA聚合酶Ⅱ (RNA polymerase Ⅱ) 转录,经剪切具有5′端帽子结构和3′端poly A尾巴,并且已被证实其序列上保守的sORF可编码微肽[5-7]。此外,由于这类微肽的分子量小、基于保守性分析的筛选机制以及检测技术水平的限制,导致其常被人们忽略,而这可能造成许多极其重要的调控机制被“隐藏”,所以这类微肽的表征就显得尤为重要。
早在2002年,具有编码能力的lncRNA就已崭露头角。Rohrig等[8]在豆类根瘤器官中发现一种含有两个sORF的lncRNA,并且其编码的微肽可以与蔗糖合酶结合。2007年,Galindo和Kondo两个团队分别发现多个与果蝇胚胎发育相关的微肽,并且这些微肽由lncRNA的sORF编码[9-10]。2008年到2010年,有多个研究团队发现由lncRNA编码的微肽还能通过参与机体的免疫过程,调控癌症的发生与发展[11-12]。2015年,Tonkin等[13]发现在改善肌肉生理性能方面,lncRNA编码的微肽同样扮演着重要角色,并可作为改善肌肉性能的药物靶点。而在近五年,人们对lncRNA编码微肽这一机制的研究更是如雨后春笋般涌现,并取得许多开创性的成果。而在这些研究中发现,由lncRNA编码的微肽可通过参与Ca2+转运[14-15]、废物降解[16-17]、线粒体代谢调控[18]、转录调控[19]、翻译调控[20]、mRNA剪接[21]、信号传导[22-24]、肌细胞融合[25]和细胞衰老[26]等过程,调节机体的稳态、癌症和疾病的发生与发展、胚胎发育等重要生理过程(图 1)。此外,由lncRNA编码的微肽更是与多种人类常见癌症发生与发展密切相关,其可通过充当抑癌因子或致癌因子影响癌症的发展,这一发现可为日后靶向治疗提供极具价值的策略。可见,lncRNA编码的微肽在生物体调控过程中扮演着重要的角色,对其深入的解析将有助于人们重新认识机体内深层的调控机理,并对微肽类靶向治疗药物的研发以及相应的临床治疗提供有价值的策略。
本文描述了由lncRNA编码的功能性微肽在肌肉生理调控、炎症免疫调节、疾病和癌症的发生与发展、昆虫及脊椎动物的胚胎发育等过程的最新研究进展,并对微肽领域现阶段面临的问题和存在的挑战进行了简单阐述,旨在为未来微肽领域的发展提供有价值的科学参考及研究思路。
1 lncRNA编码微肽的驱动机制越来越多的证据表明,大多数lncRNA具有一个或多个sORF,并且这些sORF是lncRNA编码微肽的前提。sORF的长度小于300 nt,是从起始密码子(ATG或AUG) 开始延伸到终止密码子的核酸序列,通常位于非编码序列上,如lncRNA、circRNA和pri-miRNA等[6, 27-28]。通过ORF Finder、CPC2、CNIT等一系列ORF预测及编码潜力鉴定计算工具和Ribo-seq、RNC-seq等翻译组学等现代数据分析及测序手段发现,sORF可在不同物种中被翻译,并且越长的sORF越容易被翻译[4, 29-35]。此外,sORF的翻译过程还受到IRES、m6A修饰的保守位点等开放阅读框上游的调控元件介导[6]。其中,内部核糖体进入位点(internal ribosome entry sites, IRES) 是一种独特的RNA调控元件,它可使具有sORF结构的RNA招募核糖体并驱动蛋白质合成,并且IRES不同于依赖于m7G帽子结构的翻译机制的经典真核翻译起始途径的高度复杂性,其通过与真核起始因子结合发挥作用并促进翻译起始[36-37]。此外,m6A修饰的保守位点被发现可以驱动内源ncRNA的翻译,并且在许多可翻译的内源环状RNA (circular RNA, circRNA) 中也含有m6A位点[38],因此m6A修饰的保守位点可能也是驱动lncRNA翻译的关键调控元件。此外,在研究中发现翻译的lncRNA优先定位于细胞质,而非翻译的lncRNA则优先定位于细胞核。并且细胞质lncRNA的翻译效率几乎与mRNA的翻译效率相当,而且具有翻译能力的lncRNA的sORF被核糖体所占据[39-40]。并且核糖体占据的lncRNA与没有核糖体占据的lncRNA相比具有显著独特的翻译特性[41]。表明具有编码潜力的lncRNA在细胞质中被翻译,并且其翻译与其sORF被核糖体占据这一机制密切相关。lncRNA编码微肽的机制示意图如图 1所示。
![]() |
图 1 微肽的各种生物学功能及机制示意图 Fig. 1 Schematic diagram of the various biological functions of micro-peptides. A: Ca2+ transport: MLN and DWORF respectively mediate Ca2+ transport by inhibiting or activating SERCA; B: waste degradation: SPAR regulates waste degradation by lysosomes; C: mitochondrial regulation: Mtln promotes mitochondrial Ca2+ transport, MOXI binds to mitochondrial trifunctional protein in mitochondrial inner membrane to regulate mitochondrial metabolism; D: transcriptional regulation. lncRNA Six1-encoded micro-peptide activates Six1 gene transcription; E: translation regulation: TGF-β inhibits LINC00665-encoded CIP2A-BP; F: mRNA splicing: SRSP interacts with multiple splicing regulators to regulate mRNA splicing; G: signaling: SMIM30 activates signaling by driving membrane anchoring of the non-receptor tyrosine kinase SRC/YES1, micro-peptides conduct intercellular signaling through extracellular vesicles (EVs), toddler activates signaling by driving internalization of signaling receptors. |
|
骨骼肌是人体运动系统中最大也是最重要的构成组织,在机体运动和糖脂代谢稳态调控方面发挥着关键作用[42]。肌浆/内质网Ca2+ ATP酶(sarcoplasmic reticulum Ca2+ ATPase, SERCA) 是一种可将Ca2+从细胞质转运至肌浆网(sarcoplasmic reticulum, SR) 的膜泵,其通过调控肌细胞内的Ca2+稳态控制肌肉收缩与舒张状态,从而影响肌肉生理学功能[43]。2015年,Anderson等[14]在研究骨骼肌的生理功能中发现一种由骨骼肌特异性lncRNA编码的保守肽MLN (myoregulin),该肽与PLN (phospholamban)和SLN (sarcolipin) 具有相似的结构和功能。MLN可通过直接与SERCA结合阻碍Ca2+吸收至SR,从而控制肌肉的舒张机制[14]。并且缺失MLN可增强骨骼肌中Ca2+处理能力并提高运动表现[13]。表明MLN是骨骼肌生理学功能中重要的调节器。随后,该团队在MLN研究的基础上又发现了另外两种跨膜微肽ELN (endoregulin) 和ALN (another-regulin),它们与MLN一样都是通过抑制SERCA阻碍Ca2+吸收至SR,从而控制肌肉的状态[44]。Anderson团队的这两个研究揭示了SERCA抑制性微肽家族在肌肉和非肌肉细胞类型中控制细胞内Ca2+动力学的保守机制。Nelson等[15]发现一种定位于SR膜的微肽DWORF,其由肌肉特异性lncRNA编码。该微肽可通过置换SERCA抑制剂、PLN、SLN和MLN增强SERCA活性[15]。此外,DWORF对SERCA具有比PLN更高的表观结合亲和力,并且过表达的DWORF可减轻与过表达PLN相关的收缩功能障碍[45]。通过扩张型心肌病小鼠模型发现,DWORF可增强扩张型心肌病小鼠的心收缩力并预防心力衰竭,减轻小鼠的心肌病[46]。这些数据表明DWORF有望成为一种极具吸引力的心衰治疗候选药物。综上所述,lncRNA编码的功能性微肽可通过充当SERCA的激活剂或抑制剂调控SERCA转运Ca2+这一过程,调节肌肉生理学状态,并且这一规律可为日后相关治疗药物的研发提供理论支持(图 2A)。
![]() |
图 2 肌肉相关微肽调控机制示意图 Fig. 2 Schematic diagram of the regulatory mechanism of muscle-related micro-peptides. (A) DWORF activates SERCA activity to promote Ca2+ uptake to SR, and MLN, PLN, SLN, ELN and ALN inhibit SERCA activity to prevent Ca2+ uptake to SR. (B) SPAR binding to v-ATPase prevents mTORC1 from being recruited to the lysosomal surface during amino acid stimulation or deprivation. |
|
雷帕霉素靶蛋白复合物1 (mechanistic target of rapamycin complex 1, mTORC1) 是真核细胞中高度保守的丝氨酸/苏氨酸蛋白激酶复合物,可以在生长因子、营养因素等调控下,促进细胞生长,抑制细胞自噬等过程[47-48]。2017年,Matsumoto等[16]在急性损伤后的骨骼肌中发现LINC00961可编码一种在人和小鼠之间保守的微肽,称为氨基酸反应小调节肽(small regulatory polypeptide of amino acid response, SPAR)。该微肽可在氨基酸匮乏或刺激下,使溶酶体处的v-ATPase和Regulator复合物保持紧密结合的状态,从而导致mTORC1无法募集至溶酶体表面,抑制mTORC1的激活(图 2B)[16]。而mTORC1的激活能有效地促进肌肉再生,表明在急性损伤后骨骼肌的肌肉再生中SPAR充当着抑制剂的作用[49-50]。
2.3 与线粒体代谢调控相关的微肽线粒体是机体运动的重要供能细胞器,在肌肉中大量存在,并在肌肉运动能力的表现上起关键作用。2018年,Makarewich等[18]在肌肉组织中发现一种可增强脂肪酸β-氧化的线粒体微肽MOXI (micro-peptide regulator of beta- oxidation),其由一种分别在小鼠和人类基因组中注释为1500011K16Rik和LINC00116的lncRNA编码。该微肽可在线粒体内膜与线粒体三功能蛋白(mitochondrial trifunctional protein) 结合,形成一种在脂肪酸β-氧化中起关键作用的酶复合物[18]。在敲除MOXI的小鼠模型中发现心脏和骨骼肌线粒体表现出代谢脂肪酸能力减弱,并伴随着运动能力显著降低的现象,突出了MOXI在代谢调控中的作用[18]。同年,Stein等[17]在骨骼肌和心脏中发现一种可编码微肽的LINC00116,其编码一种线粒体调节肽(mitoregulin, Mtln)。该微肽在线粒体内膜通过与心磷脂(cardiolipin) 结合,维持膜和嵌入包括呼吸超复合物在内的蛋白质复合物的结构完整性,以及支持蛋白质复合物的组装,提高线粒体的呼吸效率[17]。过表达Mtln可使线粒体膜电位、呼吸速率和Ca2+保留能力增加,线粒体活性氧(reactive oxygen species, ROS) 和无基质Ca2+减少,而这些结果与呼吸链复合、超级复合和耦合的改善相一致[51]。这表明Mtln可通过支持蛋白质复合物组装和/或稳定性提高呼吸效率。肌源性分化是肌肉发育和再生过程中的一个重要事件。2019年,Lin等[52]在肌肉中发现一种定位在线粒体的微肽MPM,其可通过促进PGC-1alpha基因(线粒体呼吸相关基因) 表达增强线粒体生物发生和线粒体呼吸,并促使线粒体的耗氧量和ATP产生增加,从而刺激肌源性分化和肌肉纤维生长,提高肌肉的运动能力。表明MPM可能是肌原分化、骨骼肌发育和再生的新促进剂,并可能成为抗肌肉萎缩症和抗衰老的潜在治疗靶点。综上所述,lncRNA编码的微肽可通过调控线粒体代谢、线粒体呼吸活动及线粒体内蛋白质复合物的组装等过程,影响心脏和肌肉的生理状态。
2.4 与肌细胞融合相关的微肽成肌细胞融合是一个关键过程,有助于肌肉在发育过程中的生长和损伤后肌纤维的再生[53]。2017年,Bi等[54]发现一种含84个氨基酸的肌肉特异性微肽myomixer,该微肽的表达与成肌细胞分化相关,对胚胎发生过程中的融合和骨骼肌形成至关重要。myomixer可促进成肌细胞融合,并与融合膜蛋白myomaker结合诱导成纤维细胞-成纤维细胞融合和成纤维细胞-成肌细胞融合[55]。表明myomaker和myomixer是哺乳动物成肌细胞融合重要的驱动因素。并且单独的myomaker不仅不足以驱动成肌细胞融合,还会消除干细胞群融合并阻止肌肉再生,从而导致损伤后严重的肌肉退化[56]。这点表明在肌肉再生和细胞融合过程中,myomaker和myomixer是重要的结合伴侣,两者通过相互协同调控肌细胞融合过程。Zhang等[25]在研究中发现另一种可与myomaker共表达并诱导伴随快速细胞骨架重排的细胞融合的微肽minion (microprotein inducer of fusion),该微肽由LOC101929726编码。并且缺乏minion的肌源性祖细胞(myogenic progenitors) 正常分化但无法形成合胞体肌管(syncytial myotubes)[25],表明Minion在肌肉发育过程中的重要性,并定义了诱导哺乳动物细胞融合的双组分程序。
2.5 其他与肌肉调控相关的微肽2013年,Magny等[57]在果蝇心脏中发现两种可通过调节钙转运影响肌肉规律收缩的微肽,这些微肽似乎从苍蝇到人类的一系列物种中保存了超过5.5亿年,并且与心脏病有关。2017年,Cai等[19]在肌肉组织中发现一种双功能lncRNA Six1,该lncRNA一方面可对编码蛋白质的Six1基因进行顺式调控,另一方面编码的微肽可激活Six1基因促进Six1表达,同时两方面皆可促进细胞增殖并参与肌肉生长过程。2020年,Wang等[58]发现,一种在脊椎动物中高度保守的微肽LEMP (lncRNA encoded micropeptide),其由lncRNA MyolncR4 (1500011K16RIK) 编码,并且缺乏该微肽可使小鼠的肌肉形成和再生过程受阻,以及斑马鱼体节的肌肉发育受损(图 2)。综上所述,在果蝇、小鼠和斑马鱼的肌肉分化中进化保守的微肽发挥着重要作用,并且这一不断增长的微肽家族的功能具有极其重要的作用。
3 与炎症免疫相关的微肽炎症是涉及多种心血管疾病(cardiovascular diseases, CVDs) 的重要过程,而含有nod-like受体家族Pyrin域3 (nod-like receptor family pyrin domain containing 3,NLRP3) 炎性小体是先天免疫和炎症的重要参与者[59]。2020年,Bhatta等[60]在小鼠巨噬细胞中发现一种lncRNA 1810058I24Rik,它在暴露于脂多糖(lipopolysaccharide, LPS) 以及其他Toll样受体(Toll-like receptors, TLR) 和炎症细胞因子的人和鼠骨髓细胞中被下调。并且其编码的线粒体微肽-47 (mitochondrial micropeptide-47, Mm47) 被证实可激活NLRP3炎性小体,参与机体的先天免疫反应和炎症进程。此外,由lncRNA编码的微肽还与细胞的抗原呈递和T细胞启动有关。Niu等[61]在人类上发现一种由lncRNA MIR155HG编码的微肽miPEP155 (P155),该微肽在炎症抗原呈递细胞中高度表达,并通过与树突状细胞(dendritic cells, DC) 中抗原运输和呈递所需的伴侣,热休克同源蛋白70 (heat shock cognate protein 70, HSC70) 的腺苷-5′-三磷酸酯结合域相互作用破坏HSC70-HSP90机制,从而调节细胞的抗原呈递和T细胞启动。而外源性注射P155被发现可以改善两种经典DC驱动的自身炎症小鼠模型,这证明一种被注释为“非蛋白编码”的转录本编码的微肽的内源性存在,并且这种微肽可作为抗原呈递的调节剂和炎症性疾病的抑制剂,用于炎症性疾病的靶向治疗[61]。此外,Jackson等[62]在研究炎症的先天免疫中发现一种微肽,该微肽可在炎症性肠病小鼠模型中产生针对感染和炎症的先天免疫反应。有趣的是该微肽是由一种包含非规范ORF的lncRNA Aw112010编码,因此将包含非规范ORF的基因错误注释为非编码RNA可能会掩盖大量以前未发现的蛋白质编码基因在免疫和疾病中的重要作用[62]。
4 与癌症相关的微肽真核转录物的很大一部分被认为是lncRNA,可调节各种癌症特征。越来越多的证据表明lncRNA包含sORF,这些sORF可被翻译成具有功能的微肽。研究表明,这些功能性微肽而非lncRNA本身对人类疾病及癌症起着关键的调控作用,并且可为疾病及癌症治疗提供宝贵的方法及理论依据。但由于现阶段技术水平等因素的限制,这些功能性微肽与人类疾病及癌症之间的关联在很大程度上仍然未知。此外,现阶段lncRNA编码的微肽主要在这些癌症中被研究:黑色素瘤、结肠癌、乳腺癌、胶质瘤、肝细胞癌、食管鳞状细胞癌、肺癌、头颈鳞癌和急性髓性白血病等。
4.1 黑色素瘤黑色素瘤(melanoma) 是一种恶性程度最高的皮肤癌类型[63]。在2008年到2010年,研究者相继在黑色素瘤细胞中发现MELOE-1和MELOE-2两种微肽,该两种微肽都由lncRNA meloe (melanoma-overexpressed antigen) 的IRES依赖性翻译[64] (图 3A)。并且在研究中发现MELOE-1和MELOE-2与黑色素瘤患者的复发预防相关。Godet等[11]将输注含有MELOE-1特异性T细胞的肿瘤浸润性淋巴细胞(tumor- infiltrating lymphocyte, TILs) 与人类组织相容性白细胞抗原A2 (human histocompatibility leukocyte antigen A2, HLA-A2) 患者的复发预防之间进行关联分析发现,9名没有复发的患者中,有5名输注了含有MELOE-1特异性T细胞的TIL,而21名复发的患者中,有0名输注了这种含有TIL的淋巴细胞。Godet等[12]在输注了TIL治疗后没有复发的病人的TIL群体中也检测到MELOE-2反应性T细胞的存在。这些结果表明,meloe编码的这类黑色素瘤抗原可能通过参与T细胞免疫监视过程,减少患者的复发概率,这可为黑色素瘤免疫治疗提供一种极具吸引力的方案。
![]() |
图 3 lncRNA编码的微肽在癌症中的调控机制示意图 Fig. 3 Schematic diagram of the regulatory mechanism of lncRNA-encoded micro-peptides in cancer. (A) The micro-peptides MELOE-1 and MELOE-2 encoded by lncRNA meloe are involved in melanoma immunotherapy by participating in the T cell immune surveillance process. (B) The micro-peptide HOXB-AS3 (aa) encoded by lncRNA HOXB-AS3 inhibits the malignant growth of CRC by interacting with hnRNP A1. (C) The micro-peptide FORCP encoded by LINC00675 inhibits the malignant growth of CRC by responding to endoplasmic reticulum stress. (D) The micro-peptide SRSP encoded by LOC90024 promotes the malignant growth of CRC by interacting with serine- and arginine-rich splicing factor 3 (SRSF3). (E) The micro-peptide RBRP encoded by LINC00266-1 promotes the malignant growth of CRC by interacting with IGF2BP1. (F) The micro-peptide ASAP encoded by LINC00467 regulates ATP synthase activity by interacting with α and γ subunits (ATP5A and ATP5C), and promotes the malignant development of colorectal cancer. (G) The micro-peptide CASIMO1 encoded by lncRNA NR_029453 promotes the malignant growth of BC by interacting with SQLE. (H) lncRNA CTD-2256P15.2 encodes a micro-peptide PACMP that inhibits ubiquitinated degradation of CtIP (CTBP-interacting protein) by binding to Cullin3-KLHL15 to promote DNA end resection on the one hand, and enhances RARylation by binding to RARP1 on the other hand, thereby regulating DNA repair, breast cancer cell survival and drug resistance. (I) The micro-peptide ASRPS encoded by LINC00908 inhibits the malignant growth of TNBC by interacting with STAT3. (J) The micro-peptide CIP2A-BP encoded by LINC00665 inhibits the malignant growth of TNBC by combining with the oncogene CIP2A. (K) The micro-peptide SMIM30 encoded by LINC00998 promotes the malignant development of HCC by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. (L) The micro-peptide KRASIM encoded by lncRNA NCBP2-AS2 inhibits the malignant growth of HCC by interacting with KRAS. (M) The micro-peptide encoded by lncRNA HBVPTPAP induces apoptosis of HCC cells by activating the JAK/STAT signaling pathway. (N) The micro-peptide PINT87aa encoded by LINC-PINT induces senescence of HCC cells by binding to FOXM1. (O) The micro-peptide MIAC encoded by lncRNA RP11-469H8.6 inhibits the malignant development of HNSCC by interacting with aquaporin 2. (P) The micro-peptide APPLE encoded by lncRNA AHS1L-AS1 enhances translation initiation by interacting with PABPC1-eIF4G and promotes the malignant development of AML. |
|
结直肠癌(colorectal cancer, CRC) 是胃肠道常见的恶性肿瘤[65]。2017年,Huang等[66]在CRC组织中发现一种可抑制CRC恶性发展的微肽,该微肽由lncRNA HOXB-AS3编码。并且该微肽通过与异型核糖核酸蛋白A1 (heterogeneous nuclear ribonucleoprotein A1, hnRNP A1) RGG基序中的甘氨酸残基竞争性结合,拮抗由hnRNP A1介导的丙酮酸激酶M (pyruvate kinase M, PKM) 剪接调节,从而调控癌症代谢重编程过程影响癌症的恶性发展[66] (图 3B)。而另一种由肠道特异性LINC00675编码的抑制癌症恶性发展的微肽FORCP (FOXA1-regulated conserved small protein),其主要通过响应内质网应激调节CRC细胞凋亡这一过程发挥抑癌作用[67] (图 3C)。此外,由lncRNA编码的微肽在CRC中还可以充当致癌因子促进癌症的进展。2020年,Meng等[21]在晚期结直肠癌中发现一种可通过与多种剪接调节因子相互作用促进癌症恶性发展的微肽SRSP (splicing regulatory small protein),其由LOC90024编码(图 3D)。并且在同一年Zhu等也在CRC中发现一种由LINC00266-1编码的微肽RBRP (RNA-binding regulatory peptide),该微肽可通过与胰岛素样生长因子-2 mRNA结合蛋白1 (insulin-like growth factor-2 mRNA- binding protein 1, IGF2BP1) 相互作用促进肿瘤恶性发展[68] (图 3E)。2021年,Ge等[69]在CRC中鉴定一种由LINC00467编码的微肽ASAP (ATP synthase-associated peptide),其通过与α和γ亚基(ATP5A和ATP5C) 相互作用增强ATP合酶的构建,从而增加ATP合酶活性和线粒体耗氧率,促进CRC细胞增殖(图 3F)。综上所述,lncRNA编码的微肽可在CRC发生与发展过程中充当抑癌因子或致癌因子起调控作用。
4.3 乳腺癌乳腺癌(breast cancer,BC) 是恶性组织在乳腺组织内形成的一种疾病[70]。2018年,Polycarpou-Schwarz等[71]在BC中发现一种由lncRNA编码的微肽CASIMO1 (cancer-associated small integral membrane open reading frame 1),该微肽在激素受体阳性的乳腺肿瘤中高表达(图 3G)。并且该微肽可通过与调节脂滴形成的BC致癌基因角鲨烯环氧化酶(squalene epoxidase, SQLE) 相互作用,调节细胞脂质稳态并介导BC的恶性发展[71]。2022年,Zhang等[72]在BC中发现一种由lncRNA CTD-2256P15.2编码的微肽PACMP (PAR-amplifying and CtIP- maintaining micropeptide),该微肽通过调控DNA损伤应答过程影响肿瘤的发展和耐药(图 3H)。并且靶向PACMP能导致DNA同源重组修复缺陷,促进肿瘤细胞对放疗、化疗、靶向治疗等多种药物的敏感性,并明显改善肿瘤疗效[72]。三阴性乳腺癌(triple negative breast cancer, TNBC) 是BC的一种亚型,其具有最具侵袭性的表型和较差的总体生存率[73]。Wang等[74]在TNBC组织中鉴定出一种由LINC00908编码的微肽ASRPS (a small regulatory peptide of STAT3),该微肽在TNBC中表达下调并与较差的总体生存率相关。此外,该微肽可通过抑制TNBC的血管生成,抑制TNBC的恶性发展[74] (图 3I)。表明LINC00908编码的微肽ASRPS可作为TNBC特异性治疗靶点。2022年,Wu等[75]在TNBC组织中发现另外一种与TNBC的血管生成和转移相关的微肽XBP1SBM (XBP1s binding micropeptide),其由lncRNA MLLT4-AS1编码。主要通过改善TNBC中的谷氨酰胺(glutamine, Gln) 水平促进血管生成和转移,从而促进TNBC的恶性发展。有研究表明,转化生长因子-β (transforming growth factor- β, TGF-β) 信号通路在BC转移中起关键作用,并且发现TGF-β主要通过调控lncRNA转录与翻译过程调控肿瘤的进展。由LINC00665编码的微肽CIP2A-BP (CIP2A binding peptide),其可通过与癌性蛋白磷酸酶2A抑制剂(Cancerous inhibitor of protein phosphatase 2A, CIP2A)结合抑制TNBC的恶性发展[20] (图 3J)。但在TNBC细胞系中CIP2A-BP的翻译被TGF-β下调,这使得癌症向恶性发展,而这一过程的发生主要是由于TGF-β激活的Smad信号通路诱导的翻译抑制蛋白4E结合蛋白1 (4E-binding protein 1,4E-BP1) 抑制翻译起始因子真核生物启动因子4E (eukaryotic initiation factor 4E,elF4E) 导致的[20]。这提示着在TNBC的发展中TGF-β可能扮演重要的致癌作用,并且可为日后CIP2A- BP在TNBC的靶向治疗提供新的方法。
4.4 胶质瘤胶质瘤(glioma) 是一种致命的恶性脑癌。许多报道表明水和离子通道的行为异常在调节肿瘤增殖、迁移、凋亡和分化中起关键作用[76-77]。研究发现一些含有sORF的lncRNA可编码形成用于水或离子调节的寡聚体微肽。然而,由于微肽肽段难以识别,导致其功能机制还远未被清楚了解。2021年,Cao等[77]在胶质瘤中发现一种可编码形成五聚体通道的微肽的lncRNA DLEU1,其包含两个sORF (ORF1和ORF8)。在模拟水和离子(Na+和Cl−) 通过该五聚体通道的传输机制的预测模型中,发现ORF1编码的肽五聚体可作为一个自组装的水通道而不是离子通道,而ORF8则既不渗透离子也不渗透水[77]。表明lncRNA编码的微肽在水和离子通道的调节中起着重要作用,这可为后续胶质瘤的治疗及药物开发提供方法和理论的支持。值得注意的是,许多lncRNA被选择性地分类到细胞外囊泡(extracellular vesicles, EVs) 中,并以多种方式调节癌症的发生和发展[78]。因此,微肽是否也可以与EVs一起发挥作用(例如传播分子和信号),从而改变或调节局部或远距离的受体细胞。在2021年,Cai等[24]从神经胶质瘤癌EVs中鉴定出一类长度介于20−100个氨基酸的微肽,其由lncRNA编码。并且研究人员分别从构建的胶质瘤患者和健康受试者的EVs微肽表达谱中,鉴定出了64种和48种微肽。对两者进行对比,发现癌症患者中缺少17种微肽,但检测到19个新的微肽,表明两者表达谱存在显著差异,暗示EVs中的微肽可能在识别胶质瘤患者方面具有潜在的诊断应用[24]。此外,研究者在检查人血浆时,分别从纯化的EVs、全血浆和不含EVs的血浆中鉴定出48、11和3种微肽,表明微肽主要富含于EVs中,并且由EVs介导的微生物蛋白转移可能代表了一种新的细胞间通讯机制[24]。2021年,Huang等[79]在胶质母细胞瘤(glioblastoma, GBM) 中发现一种由磷酸酶和张力蛋白同源物(phosphatase and tensin homolog, PTEN) 上游开放阅读框(upstream open reading frame, uORF) 编码的微肽MP31,该微肽通过与线粒体乳酸脱氢酶(mitochondrial lactate dehydrogenase, mLDH) 竞争,限制线粒体中乳酸-丙酮酸转化烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD+)。此外,研究者在敲除MP31的小鼠体内发现乳酸代谢整体被增强,而敲除MP31的星形胶质细胞中,显示出胶质瘤生成被激活和动物的总体存活时间被缩短的情况[79]。这些结果表明,GBM中MP31可通过协调乳酸代谢重编程过程,调控胶质母细胞瘤的恶性进展。
4.5 肝细胞癌肝细胞癌(hepatocellular carcinoma, HCC) 是一种始发于肝脏的恶性肿瘤[80]。2020年,Pang等[23]发现癌细胞中有许多lncRNA可与核糖体蛋白S6 (ribosomal protein S6, RPS6) 结合,并且这些lncRNA具有编码微肽的潜能。其中LINC00998被广泛关注,并在研究中发现LINC00998可编码一种含59个氨基酸的保守肽SMIM30 (small integral membrane protein 30)[23] (图 3K)。该微肽可通过调节细胞增殖和迁移促进HCC的肿瘤发生,而且这一调控过程与lncRNA本身无关,表明SMIM30具有独立的功能[23]。另一种具有独立功能的微肽KRASIM (KRAS-interacting microprotein),其由lncRNA NCBP2-AS2编码,并通过与Kirsten大鼠肉瘤病毒癌基因同源物(Kirsten ratsarcoma viral oncogene homolog, KRAS) 相互作用降低KRAS的蛋白水平,从而抑制HCC细胞中致癌信号的传导[81](图 3L)。表明KRASIM是一种KRAS通路的新型微生物蛋白抑制剂,可为致癌信号调节和HCC治疗提供有价值的策略。另外,诱导癌细胞凋亡也是微肽抑制癌症向恶性发展的重要方式。由lncRNA HBVPTPAP编码的微肽通过调节Janus酪氨酸激酶/信号转导与转录激活子(Janus tyrosine kinase/signal transducer and activator of tran-ions, JAK/STAT) 信号通路诱导HCC细胞凋亡,从而抑制HCC恶性发展[82] (图 3M)。虽然已有许多已知参与人类癌症进展的lncRNA被证明可以编码具有生物学功能的肽,但是lncRNA编码的微肽在HCC细胞衰老中的作用很大程度上仍是未知。Xiang等[26]报道了一种在HCC细胞衰老中起重要作用的微肽PINT87aa (p53-induced transcript 87aa),该微肽由LINC-PINT编码。PINT87aa在过氧化氢诱导的HCC细胞衰老模型中显著上调,并且过表达的PINT87aa可诱导生长抑制、细胞衰老和减少线粒体自噬(图 3N)。这一结果表明PINT87aa可能成为日后HCC治疗的潜在靶点和预后的新型生物标志物。此外,LINC- PINT的第二个外显子可通过自环化形成环状分子circPINT,并编码功能性微肽PINT87aa。而该微肽可直接与聚合酶相关因子复合物(polymerase associated factor complex, PAF1c) 相互作用抑制多个癌基因的转录延长,从而抑制胶质母细胞瘤肿瘤细胞增殖[83]。表明LINC- PINT在癌症的发生和发展中起着重要作用,可作为日后癌症治疗及预后的生物标志物。
4.6 食管鳞状细胞癌食管鳞状细胞癌(esophageal squamous cell carcinoma, ESCC) 是食管癌中最常见的病理类型,约占食管癌的90%,是一种临床比较严重的疾病[84]。然而,ESCC与lncRNA编码的微肽之间的关联在很大程度上仍然未知。2020年,Wu等[85]在男性ESCC中表征了一种Y连锁的LINC00278,该lncRNA第一个外显子的sORF可编码一种阴阳1结合微肽(Yin Yang 1 binding micropeptide, YY1BM),并且该微肽是一种潜在的抗癌因子。由吸烟诱导的ALKBH5蛋白可通过介导lncRNA m6A去甲基化,降低LINC00278的sORF翻译效率[85]。此外,YY1BM可参与ESCC进展并抑制YY1和雄激素受体(androgen receptor, AR) 之间的相互作用,从而通过AR信号通路降低真核延伸因子-2激酶(eukaryotic elongation factor-2 kinase, eEF2K) 的表达[86]。因此YY1BM的下调可显著上调eEF2K表达并抑制细胞凋亡,从而使ESCC细胞更适应营养缺乏状态。这些结果提示了吸烟与男性ESCC进展中AR信号传导之间的机制联系,当由吸烟诱导的Y染色体相关的lncRNA m6A去甲基化时,男性患癌症的风险增加。
4.7 其他癌症肺癌(lung cancer) 是肺内细胞出现基因突变,出现恶性增长的过程。Lu等[87]在肺癌中发现一种定位于核仁的微肽UBAP1-AST6,其由lncRNA编码并在肺癌细胞系中表达,且与肺癌细胞的恶性增殖相关。Li等[88]在头颈部鳞状细胞癌(head and neck squamous cell carcinoma, HNSCC) 中发现由lncRNA RP11-469H8.6编码的内源性微肽MIAC (micropeptide inhibiting actin cytoskeleton),该微肽通过与水通道蛋白2 (aquaporin 2) 相互作用抑制HNSCC向恶性发展(图 3O)。此外,研究者通过结合500例TCGA数据库中HNSCC RNA-seq的数据和154例临床样本检测分析证实MIAC在HNSCC组织中表达显著低于癌旁组织,其表达水平与患者总生存率呈正相关,与临床病理分期、区域淋巴结转移呈负相关,提示MIAC可作为HNSCC临床诊断和预后的潜在标志物[88]。急性髓性白血病(acute myeloid leukemia, AML) 是一种造血系统恶性肿瘤,源于骨髓内恶性造血前体细胞的克隆性扩增[89-90]。2021年,Sun等[91]在AML中发现一种由lncRNA AHS1L- AS1编码的微肽APPLE (a peptide located in ER)。该微肽在AML中高表达,并通过促进聚腺苷酸结合蛋白细胞质1 (polyadenylate- binding protein cytoplasmic 1, PABPC1) 与真核生物启动因子4G (eukaryotic initiation factor 4G, eIF4G) 相互作用、mRNA环化以及eIF4F起始复合物组装,以支持特定的促癌翻译程序,从而促进造血系统恶性肿瘤的发展[91](图 3P)。该研究所提供的证据表明,通过靶向APPLE可为AML的潜在靶向治疗提供新的治疗策略。
5 与其他疾病相关微肽肺动脉高压(pulmonary hypertension, PH) 是一种罕见且致命的疾病,由缺氧引起的肺动脉平滑肌细胞(pulmonary artery smooth muscle cells, PASMCs) 增殖是PH的重要病理过程,并且防止PASMCs增殖可有效降低PH死亡率[92]。Liu等[93]在缺氧小鼠模型中发现一种具有高编码能力的lnc-Rps4l,其在低氧条件下可介导PASMCs增殖。该团队随后又发现其编码的微肽RPS4XL (ribosomal protein S4 X isoform-like) 可通过与核糖体蛋白S6 (ribosomal protein S6, RPS6) 结合调控RPS6磷酸化,抑制缺氧引起的PASMCs增殖[94]。这一发现表明具有高编码能力的lnc-Rps4l可作为缺氧PH早期诊断和治疗的潜在靶点。急性心肌梗塞(acute myocardial infarction, AML) 是冠状动脉发生急性堵塞,引起部分心肌缺血性坏死的一种严重冠心病[95]。Spencer等[96]发现一种在血管生成中起重要作用的微肽SPAAR (small regulatory polypeptide of amino acid response),其由LINC00961编码。在小鼠模型中,发现LINC00961/SPAAR基因座丢失可影响小鼠发育、心肌动力学和心肌梗死心脏反应[97]。数据表明,LINC00961/SPAAR有助于生长和发育以及成年期的基础心血管功能、减轻心肌梗塞风险。
6 胚胎发育相关微肽昆虫中的分节基因(segmentation genes) 是产生早期胚胎体节划分的必要条件。2006年,Savard等[98]发现一种面粉甲虫(Tribolium) 中分节基因间隙家族成员mlpt (mille-pattes)。敲低mlpt可导致腹节转化为胸节,为胚胎提供多达十对腿。此外,mlpt和Tribolium中已知的间隙基因之间存在交叉调节作用,并且其可转录一种含4种sORF的多顺反子mRNA,这一发现提示着由其编码的微肽可能在细胞组织发育成胚胎过程中起着关键作用,但其具体机制还有待探索[98]。Galindo等[9]在果蝇中发现一种之前被推定为非编码RNA的基因tal (tarsal- less),其可被翻译成一种只有11个氨基酸的微肽,并且该微肽可通过控制果蝇相关基因表达和组织折叠控制胚胎发育。而另一种之前在果蝇中被鉴定为非编码RNA的基因pri (polished rice),其进化上保守的sORF可编码11或32个氨基酸的微肽,并且pri在胚胎发生过程中在所有上皮组织中表达[10]。此外,pri功能的丧失完全消除了顶端角质层结构,并且还导致气管导管扩张缺陷[10]。而这个研究提供的证据表明,pri非细胞自主地起作用,并且pri上4个保守的sORF在功能上可能是冗余的。但是在随后的研究中证明,在果蝇胚胎发生过程中,由pri的sORF编码的微肽可通过修饰转录因子Svb (shavenbaby) 控制果蝇的表皮分化[99]。并且在果蝇胚胎发生过程中,pri编码的微肽可为表皮形态发生的转录程序提供严格的控制,表明pri编码的微肽在功能上并不是冗余的。此外,在果蝇表皮分化中鉴定的分子复合物,包括mlpt、泛素连接酶Ubr3和Svb,代表了早期昆虫胚胎模式化所需的古老发育模块[100]。而该模块的分节功能的丧失与早期果蝇胚胎中Svb的表达受限同时发生[100]。当人为恢复早期Svb的表达会导致依赖于mlpt功能的分节缺陷,这表明尽管胚胎模式在不断演变,但古老的发育“开关”仍具有持久的效力。这些结果突出保守的分子复合体在基本遗传网络的约束下的进化可塑性。此外,Pauli等[22]在斑马鱼胚胎发生过程中发现一种由LOC100506013编码的保守性微肽toddler,并且该微肽的缺失和过表达都会减少斑马鱼原肠胚形成过程中中内胚层细胞的运动。综上所述,微肽对果蝇和斑马鱼的胚胎发育起着关键作用,但是微肽在哺乳动物胚胎发育方面的研究还相对较少,其具体作用机制还不清晰,因此探究微肽在哺乳动物胚胎发育方面的研究将更具有挑战性。
7 问题与展望随着研究不断的深入,许多具有编码能力的lncRNA被发现,使得人们开始重新审视lncRNA在生物体中的作用。而由lncRNA编码的微肽大都独立于lncRNA在各种生物过程中发挥作用,因此在研究中应注意将微肽的功能和lncRNA本身的功能区分开。另外,在早前的研究中发现微肽可通过参与生物体细胞程序性死亡、抗原呈递、钙离子转运、线粒体代谢调控、废物降解和肌细胞融合等过程,调控机体的稳态、肌肉的生理功能、疾病和癌症的发生与发展、胚胎发育等过程(微肽功能总结见表 1)。因此,关于微肽的研究将有助于研究者对生物体生理功能的解析和对疾病及癌症靶向治疗药物的研发。
Species | lncRNA | Micro-peptide | Length (aa) |
Function | Physiological processes | References |
Soy bean | ENOD40 | ENOD40 (aa) | 12/24 | Interaction with sucrose synthase | Plant physiology | [8] |
Human/ mouse |
LINC00948/ AK009351 |
MLN | 46 | Important regulator of skeletal muscle physiology |
Muscle physiology | [14] |
Human/ mouse |
LOC100507537/ NONMMUG026737 |
DWORF | 34 | Enhances muscle contractility, prevents heart failure and attenuates cardiomyopathy in mouse; candidate drug for heart failure treatment |
Muscle physiology | [15, 46] |
Mouse | LINC00961 | SPAR | 75 | Regulate muscle regeneration | Muscle physiology | [16] |
Mouse | LOC101929726 | Myomixer | 84 | Promote myoblast fusion, regulate muscle development and muscle fiber regeneration after injury |
Muscle physiology | [54-56] |
Mouse | LOC101929726 | Minion | 84 | Control of cell fusion and muscle formation |
Muscle physiology | [25] |
Mouse | LINC00116/ 1500011K16Rik |
MOXI | 56 | Regulation of skeletal muscle mitochondrial metabolism |
Muscle physiology | [18] |
Mouse | LINC00116 | Mtln | 56 | Regulation of skeletal muscle mitochondrial metabolism |
Muscle physiology | [17] |
Mouse/ zebrafish |
MyolncR4/ 1500011K16RIK |
LEMP | 56 | Promotes muscle formation and regeneration in mouse |
Muscle physiology | [58] |
Chicken | Six1 | Six1 (aa) | 74 | Promotes cell proliferation and participates in muscle growth |
Muscle physiology | [19] |
Mouse | 1810058I24Rik | Mm47 | 47 | Controls innate immunity and influencing inflammation |
Inflammation and immunity |
[60] |
Human | MIR155HG | miPEP155 (P155) | 17 | Regulation of antigen presentation suppresses autoimmune inflammation |
Inflammation and immunity |
[61] |
Human | Meloe | MELOE-1/ MELOE-2 |
46/39 | Involved in T cell immune surveillance; optimal T cell target for melanoma immunotherapy |
Melanoma | [11-12, 64] |
Human | HOXB-AS3 | HOXB-AS3 (aa) | 53 | Modulating the process of cancer metabolic reprogramming and inhibiting colorectal cancer growth |
Colorectal cancer | [66] |
Human | LINC00675 | FORCP | 79 | Regulates colorectal cancer cell apoptosis, inhibits proliferation and tumorigenesis |
Colorectal cancer | [67] |
Human | LINC00266-1 | RBRP | 71 | Promote colorectal cancer tumorigenesis |
Colorectal cancer | [68] |
Human | LINC00467 | ASAP | 94 | Promote colorectal cancer cell proliferation |
Colorectal cancer | [69] |
Human | NR_029453 | CASIMO1 | 83 | Promote the malignant development of breast cancer |
Breast cancer | [71] |
Human | CTD-2256P15.2 | PACMP | 44 | Promote the malignant development of breast cancer |
Breast cancer | [72] |
Human | LINC00908 | ASRPS | 60 | Inhibit the malignant development of triple negative breast cancer |
Breast cancer | [74] |
Human | MLLT4-AS1 | XBP1SBM | 21 | Promote the malignant development of triple negative breast cancer |
Breast cancer | [75] |
Human | LINC00665 | CIP2A-BP | 52 | Inhibit the malignant development of triple negative breast cancer |
Breast cancer | [20] |
Human | LINC00998 | SMIM30 | 59 | Regulation of cell proliferation and migration, promotes tumorigenesis in hepatocellular carcinoma |
Hepatocellular carcinoma | [23] |
Human | NCBP2-AS2 | KRASIM | 99 | Inhibition of oncogenic signaling in hepatocellular carcinoma cells |
Hepatocellular carcinoma | [81] |
Human | LINC-PINT | PINT87aa | 87 | Induction of senescence in hepatocellular carcinoma cells; novel biomarkers and potential therapeutic targets |
Hepatocellular carcinoma | [26] |
Human | LINC00278 | YY1BM | 21 | Inhibit the malignant development of esophageal squamous cell carcinoma |
Esophageal squamous cell carcinoma |
[85] |
Human | UBAP1-AST6 | BAP1-AST6 (aa) | − | Involved in the malignant proliferation of lung cancer cells |
Lung cancer | [87] |
RP11-469H8.6 | MIAC | 51 | Inhibiting the malignant progression of Head and neck squamous cell carcinoma |
Head and neck squamous cell carcinoma |
[88] | |
Human | AHS1L-AS1 | APPLE | 90 | Promote the development of acute myeloid leukemia |
Acute myeloid leukemia |
[91] |
Human | Rps4l | RPS4XL | − | Inhibition of hypoxia-induced proliferation of pulmonary artery smooth muscle cells |
Pulmonary hypertension | [94] |
Human | LINC00961 | SPAAR | 75 | Reduce the risk of myocardial infarction | Acute myocardial infarction |
[96-97] |
Fruit fly | Pri (polished rice) | Pri (aa) | 11/32 | Control of Drosophila epidermal differentiation during Drosophila embryogenesis |
Embryonic development | [10] |
Fruit fly | Tal (tarsal-less) | Tal (aa) | 11 | Control of Drosophila-related gene expression and tissue folding and control of embryonic development |
Embryonic development | [9] |
Zebrafish | LOC100506013 | Toddler | 58 | Promotes zebrafish embryogenesis | Embryonic development | [22] |
Mouse | Gm9999 | Kastor/Polluks | 53/40 | Regulation of voltage-dependent anion channels (VDAC) and spermatogenesis |
Reproductive physiology | [101] |
在近10年的研究中发现大部分关于微肽的研究主要集中在人类疾病和癌症。并且微肽主要通过充当致癌因子或抑癌因子影响癌症的进展。当前人们致力于开发新型癌症靶向治疗药物,并从中发现微肽类靶向治疗药物,相比于当前各类化疗药物或靶向治疗药物,具有特异性和活性高、细胞毒性小、免疫原性低等优点[102-103]。所以微肽类靶向治疗药物将有可能成为一类极具吸引力的靶向治疗药物。lncRNA编码的微肽具有肽段较短、分子量小以及表达丰度低等特点,而这可能造成微肽类药物提取和合成困难以及相关检测技术无法准确识别等问题。因此相应技术的进一步优化和巧妙的实验设计,将是微肽领域取得持续进展的关键。此外,越来越多的研究发现翻译组学的发展可为微肽领域研究提供坚实的助力,其中Ribo-seq更是当前研究lncRNA编码能力的重要手段。研究者可将Ribo-seq与RNA-seq或lncRNA-seq进行联合分析,从中寻找具有编码潜力的关键lncRNA。同时在此基础上结合蛋白质组学,可对新微肽进行更深入地挖掘及佐证。并且获得的关键lncRNA也可通过相关编码潜力评估及预测工具、软件进行进一步评估与预测,从而获得更为准确可信的数据。
尽管当前不断有微肽的功能被表征和发现,但功能性微肽的筛选机制仍饱受争议。主要是由于基于保守性分析和规范化的微肽筛选机制,可能会造成大量非保守和非规范化的微肽被“隐藏”或丢弃,而这可能会造成一些在生物体调控过程中有着重要调控作用的微肽的缺失。因此如何优化当前的微肽筛选机制将是进一步推动微肽领域研究的有力举措。另外,当前注释具有编码能力的lncRNA物种数据库还相对较少,只包括人和少数几种模式动物。并且由于物种间差异,导致许多数据库不足以满足现阶段对微肽研究的要求,所以基于不同物种间功能注释数据库的建立,就显得尤为重要。此外,尽管微肽在人类和模式动物上进行了许多研究,但是在其他物种如奶牛、山羊、猪等重要的经济动物上的研究还相对较少,具体作用机制还不清晰。然而,这些经济动物在人们的生活中又是不可或缺的部分,所以关于这方面研究的推进也将是重中之重。毋庸置疑,lncRNA编码微肽这一机制将引领新的研究热潮和推动生命科学领域的发展,并且其提供的新视角将为未来抗癌药物和预后生物标志物的研究提供新的见解。
[1] |
Djebali S, Davis CA, Merkel A, et al. Landscape of transcription in human cells. Nature, 2012, 489(7414): 101-108. DOI:10.1038/nature11233
|
[2] |
Consortium ENCOEEP, Moore JE, Purcaro MJ, et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature, 2020, 583(7818): 699-710. DOI:10.1038/s41586-020-2493-4
|
[3] |
Wang JZ, Zhu S, Meng N, et al. ncRNA-encoded peptides or proteins and cancer. Mol Ther, 2019, 27(10): 1718-1725. DOI:10.1016/j.ymthe.2019.09.001
|
[4] |
Mackowiak SD, Zauber H, Bielow C, et al. Extensive identification and analysis of conserved small ORFs in animals. Genome Biol, 2015, 16: 179. DOI:10.1186/s13059-015-0742-x
|
[5] |
Statello L, Guo CJ, Chen LL, et al. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol, 2021, 22(2): 96-118. DOI:10.1038/s41580-020-00315-9
|
[6] |
Wu P, Mo YZ, Peng M, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer, 2020, 19(1): 22. DOI:10.1186/s12943-020-1147-3
|
[7] |
Li J, Liu CN. Coding or noncoding, the converging concepts of RNAs. Front Genet, 2019, 10: 496. DOI:10.3389/fgene.2019.00496
|
[8] |
Rohrig H, Schmidt J, Miklashevichs E, et al. Soybean ENOD40 encodes two peptides that bind to sucrose synthase. PNAS, 2002, 99(4): 1915-1920. DOI:10.1073/pnas.022664799
|
[9] |
Galindo MI, Pueyo JI, Fouix S, et al. Peptides encoded by short ORFs control development and define a new eukaryotic gene family. PLoS Biol, 2007, 5(5): e106. DOI:10.1371/journal.pbio.0050106
|
[10] |
Kondo T, Hashimoto Y, Kato K, et al. Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA. Nat Cell Biol, 2007, 9(6): 660-665. DOI:10.1038/ncb1595
|
[11] |
Godet Y, Moreau-Aubry A, Guilloux Y, et al. MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. J Exp Med, 2008, 205(11): 2673-2682. DOI:10.1084/jem.20081356
|
[12] |
Godet Y, Moreau-Aubry A, Mompelat D, et al. An additional ORF on Meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-specific T cells in the HLA-A2 context. Cancer Immunol Immunother, 2010, 59(3): 431-439. DOI:10.1007/s00262-009-0762-z
|
[13] |
Tonkin J, Rosenthal N. One small step for muscle: a new micropeptide regulates performance. Cell Metab, 2015, 21(4): 515-516. DOI:10.1016/j.cmet.2015.03.013
|
[14] |
Anderson DM, Anderson KM, Chang CL, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell, 2015, 160(4): 595-606. DOI:10.1016/j.cell.2015.01.009
|
[15] |
Nelson BR, Makarewich CA, Anderson DM, et al. A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science, 2016, 351(6270): 271-275. DOI:10.1126/science.aad4076
|
[16] |
Matsumoto A, Pasut A, Matsumoto M, et al. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature, 2017, 541(7636): 228-232. DOI:10.1038/nature21034
|
[17] |
Stein CS, Jadiya P, Zhang XM, et al. Mitoregulin: a lncRNA-encoded microprotein that supports mitochondrial super complexes and respiratory efficiency. Cell Rep, 2018, 23(13): 3710-3720.e8. DOI:10.1016/j.celrep.2018.06.002
|
[18] |
Makarewich CA, Baskin KK, Munir AZ, et al. MOXI is a mitochondrial micropeptide that enhances fatty acid β-oxidation. Cell Rep, 2018, 23(13): 3701-3709. DOI:10.1016/j.celrep.2018.05.058
|
[19] |
Cai BL, Li ZH, Ma MT, et al. LncRNA-Six1 encodes a micropeptide to activate Six1 in cis and is involved in cell proliferation and muscle growth. Front Physiol, 2017, 8: 230. DOI:10.3389/fphys.2017.00230
|
[20] |
Guo BB, Wu SQ, Zhu X, et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. EMBO J, 2020, 39(1): e102190.
|
[21] |
Meng N, Chen M, Chen D, et al. Small protein hidden in lncRNA LOC90024 promotes "cancerous" RNA splicing and tumorigenesis. Adv Sci (Weinh), 2020, 7(10): 1903233. DOI:10.1002/advs.201903233
|
[22] |
Pauli A, Norris ML, Valen E, et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science, 2014, 343(6172): 1248636. DOI:10.1126/science.1248636
|
[23] |
Pang YN, Liu ZY, Han H, et al. Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. J Hepatol, 2020, 73(5): 1155-1169. DOI:10.1016/j.jhep.2020.05.028
|
[24] |
Cai TX, Zhang Q, Wu BW, et al. LncRNA-encoded microproteins: a new form of cargo in cell culture-derived and circulating extracellular vesicles. J Extracell Vesicles, 2021, 10(9): e12123.
|
[25] |
Zhang Q, Vashisht AA, O'Rourke J, et al. The microprotein minion controls cell fusion and muscle formation. Nat Commun, 2017, 8: 15664. DOI:10.1038/ncomms15664
|
[26] |
Xiang XH, Fu YN, Zhao K, et al. Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2. Theranostics, 2021, 11(10): 4929-4944. DOI:10.7150/thno.55672
|
[27] |
Merry TL, Chan A, Woodhead JST, et al. Mitochondrial-derived peptides in energy metabolism. Am J Physiol Endocrinol Metab, 2020, 319(4): E659-E666. DOI:10.1152/ajpendo.00249.2020
|
[28] |
Sieber P, Platzer M, Schuster S. The definition of open reading frame revisited. Trends Genet, 2018, 34(3): 167-170. DOI:10.1016/j.tig.2017.12.009
|
[29] |
Olexiouk V, Crappé J, Verbruggen S, et al. sORFs. org: a repository of small ORFs identified by ribosome profiling. Nucleic Acids Res, 2016, 44(D1): D324-D329.
|
[30] |
Yan YC, Tang R, Li B, et al. The cardiac translational landscape reveals that micropeptides are new players involved in cardiomyocyte hypertrophy. Mol Ther, 2021, 29(7): 2253-2267. DOI:10.1016/j.ymthe.2021.03.004
|
[31] |
Mishra SK, Wang H. Computational analysis predicts hundreds of coding lncRNAs in zebrafish. Biology, 2021, 10(5): 371. DOI:10.3390/biology10050371
|
[32] |
Ruiz-Orera J, Messeguer X, Subirana JA, et al. Long non-coding RNAs as a source of new peptides. eLife, 2014, 3: e03523. DOI:10.7554/eLife.03523
|
[33] |
Zhao J, Qin B, Nikolay R, et al. Translatomics: the global view of translation. Int J Mol Sci, 2019, 20(1): 212. DOI:10.3390/ijms20010212
|
[34] |
Kang YJ, Yang DC, Kong L, et al. CPC2: a fast and accurate coding potential calculator based on sequence intrinsic features. Nucleic Acids Res, 2017, 45(W1): W12-W16. DOI:10.1093/nar/gkx428
|
[35] |
Guo JC, Fang SS, Wu Y, et al. CNIT: a fast and accurate web tool for identifying protein-coding and long non-coding transcripts based on intrinsic sequence composition. Nucleic Acids Res, 2019, 47(W1): W516-W522. DOI:10.1093/nar/gkz400
|
[36] |
Johnson AG, Grosely R, Petrov AN, et al. Dynamics of IRES-mediated translation. Phil Trans R Soc B, 2017, 372(1716): 20160177. DOI:10.1098/rstb.2016.0177
|
[37] |
Arhab Y, Bulakhov AG, Pestova TV, et al. Dissemination of internal ribosomal entry sites (IRES) between viruses by horizontal gene transfer. Viruses, 2020, 12(6): 612. DOI:10.3390/v12060612
|
[38] |
Yang Y, Fan XJ, Mao MW, et al. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res, 2017, 27(5): 626-641. DOI:10.1038/cr.2017.31
|
[39] |
Mills JD, Ward M, Chen BJ, et al. LINC00507 is specifically expressed in the primate cortex and has age-dependent expression patterns. J Mol Neurosci, 2016, 59(4): 431-439. DOI:10.1007/s12031-016-0745-4
|
[40] |
Ji Z, Song RS, Regev A, et al. Many lncRNAs, 5'UTRs, and Pseudogenes are translated and some are likely to express functional proteins. eLife, 2015, 4: e08890. DOI:10.7554/eLife.08890
|
[41] |
Wang HW, Wang Y, Xie SQ, et al. Global and cell-type specific properties of lincRNAs with ribosome occupancy. Nucleic Acids Res, 2017, 45(5): 2786-2796.
|
[42] |
Frontera WR, Ochala J. Skeletal muscle: a brief review of structure and function. Calcif Tissue Int, 2015, 96(3): 183-195. DOI:10.1007/s00223-014-9915-y
|
[43] |
Muthu P, Kumar MS, Kumar SS, et al. Role of SERCA pump in muscle thermogenesis and metabolism. Compr Physiol, 2017, 7(3): 879-890.
|
[44] |
Anderson DM, Makarewich CA, Anderson KM, et al. Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides. Sci Signal, 2016, 9(457): ra119.
|
[45] |
Makarewich CA, Munir AZ, Schiattarella GG, et al. The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy. eLife, 2018, 7: e38319. DOI:10.7554/eLife.38319
|
[46] |
Makarewich CA, Bezprozvannaya S, Gibson AM, et al. Gene therapy with the DWORF micropeptide attenuates cardiomyopathy in mice. Circ Res, 2020, 127(10): 1340-1342. DOI:10.1161/CIRCRESAHA.120.317156
|
[47] |
Cho S, Lee G, Pickering BF, et al. mTORC1 promotes cell growth via m6A-dependent mRNA degradation. Mol Cell, 2021, 81(10): 2064-2075.e8. DOI:10.1016/j.molcel.2021.03.010
|
[48] |
Villa E, Sahu U, O'Hara BP, et al. mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis. Mol Cell, 2021, 81(10): 2076-2093.e9. DOI:10.1016/j.molcel.2021.03.009
|
[49] |
Rion N, Rüegg MA. LncRNA-encoded peptides: more than translational noise. Cell Res, 2017, 27(5): 604-605. DOI:10.1038/cr.2017.35
|
[50] |
Tajbakhsh S. lncRNA-encoded polypeptide SPAR(s) with mTORC1 to regulate skeletal muscle regeneration. Cell Stem Cell, 2017, 20(4): 428-430. DOI:10.1016/j.stem.2017.03.016
|
[51] |
Chugunova A, Loseva E, Mazin P, et al. LINC00116 codes for a mitochondrial peptide linking respiration and lipid metabolism. PNAS, 2019, 116(11): 4940-4945. DOI:10.1073/pnas.1809105116
|
[52] |
Lin YF, Xiao MH, Chen HX, et al. A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation. Cell Death Dis, 2019, 10(7): 528. DOI:10.1038/s41419-019-1767-y
|
[53] |
Hindi SM, Tajrishi MM, Kumar A. Signaling mechanisms in mammalian myoblast fusion. Sci Signal, 2013, 6(272): re2.
|
[54] |
Bi PP, Ramirez-Martinez A, Li H, et al. Control of muscle formation by the fusogenic micropeptide myomixer. Science, 2017, 356(6335): 323-327. DOI:10.1126/science.aam9361
|
[55] |
Shi J, Bi PP, Pei JM, et al. Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish. Proc Natl Acad Sci USA, 2017, 114(45): 11950-11955. DOI:10.1073/pnas.1715229114
|
[56] |
Bi PP, McAnally JR, Shelton JM, et al. Fusogenic micropeptide myomixer is essential for satellite cell fusion and muscle regeneration. PNAS, 2018, 115(15): 3864-3869. DOI:10.1073/pnas.1800052115
|
[57] |
Magny EG, Pueyo JI, Pearl FMG, et al. Conserved regulation of cardiac calcium uptake by peptides encoded in small open reading frames. Science, 2013, 341(6150): 1116-1120. DOI:10.1126/science.1238802
|
[58] |
Wang LT, Fan J, Han LL, et al. The micropeptide LEMP plays an evolutionarily conserved role in myogenesis. Cell Death Dis, 2020, 11(5): 357. DOI:10.1038/s41419-020-2570-5
|
[59] |
Wang YC, Liu XX, Shi H, et al. NLRP3 inflammasome, an immune-inflammatory target in pathogenesis and treatment of cardiovascular diseases. Clin Transl Med, 2020, 10(1): 91-106. DOI:10.1002/ctm2.13
|
[60] |
Bhatta A, Atianand M, Jiang ZZ, et al. A mitochondrial micropeptide is required for activation of the Nlrp3 inflammasome. J Immunol, 2020, 204(2): 428-437. DOI:10.4049/jimmunol.1900791
|
[61] |
Niu LM, Lou FZ, Sun Y, et al. A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation. Sci Adv, 2020, 6(21): eaaz2059. DOI:10.1126/sciadv.aaz2059
|
[62] |
Jackson R, Kroehling L, Khitun A, et al. The translation of non-canonical open reading frames controls mucosal immunity. Nature, 2018, 564(7736): 434-438. DOI:10.1038/s41586-018-0794-7
|
[63] |
Sanchez JA, Robinson WA. Malignant melanoma. Annu Rev Med, 1993, 44: 335-342. DOI:10.1146/annurev.me.44.020193.002003
|
[64] |
Charpentier M, Dupré E, Fortun A, et al. hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote MELOE-1 translation in stressed melanoma cells. Mol Oncol, 2022, 16(3): 594-606. DOI:10.1002/1878-0261.13088
|
[65] |
Montalban-Arques A, Scharl M. Intestinal microbiota and colorectal carcinoma: implications for pathogenesis, diagnosis, and therapy. EBioMedicine, 2019, 48: 648-655. DOI:10.1016/j.ebiom.2019.09.050
|
[66] |
Huang JZ, Chen M, Chen D, et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses colon cancer growth. Mol Cell, 2017, 68(1): 171-184.e6. DOI:10.1016/j.molcel.2017.09.015
|
[67] |
Li XL, Pongor L, Tang W, et al. A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells. eLife, 2020, 9: e53734. DOI:10.7554/eLife.53734
|
[68] |
Zhu S, Wang JZ, Chen D, et al. An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis. Nat Commun, 2020, 11(1): 1685. DOI:10.1038/s41467-020-15403-9
|
[69] |
Ge QW, Jia D, Cen D, et al. Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity. J Clin Invest, 2021, 131(22): e152911. DOI:10.1172/JCI152911
|
[70] |
Liang YR, Zhang HW, Song XJ, et al. Metastatic heterogeneity of breast cancer: molecular mechanism and potential therapeutic targets. Semin Cancer Biol, 2020, 60: 14-27. DOI:10.1016/j.semcancer.2019.08.012
|
[71] |
Polycarpou-Schwarz M, Groß M, Mestdagh P, et al. The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. Oncogene, 2018, 37(34): 4750-4768. DOI:10.1038/s41388-018-0281-5
|
[72] |
Zhang C, Zhou B, Gu F, et al. Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation. Mol Cell, 2022: 2022Feb17;S1097-2022Feb17;S2765(22)00085-5.
|
[73] |
Vagia E, Mahalingam D, Cristofanilli M. The landscape of targeted therapies in TNBC. Cancers, 2020, 12(4): 916. DOI:10.3390/cancers12040916
|
[74] |
Wang YR, Wu SQ, Zhu X, et al. LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis. J Exp Med, 2020, 217(3): jem.20190950. DOI:10.1084/jem.20190950
|
[75] |
Wu S, Guo B, Zhang L, et al. A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway. Oncogene, 2022, 2022Feb23.
|
[76] |
Stroka KM, Jiang HY, Chen SH, et al. Water permeation drives tumor cell migration in confined microenvironments. Cell, 2014, 157(3): 611-623. DOI:10.1016/j.cell.2014.02.052
|
[77] |
Cao YP, Yang R, Lee I, et al. Prediction of lncRNA-encoded small peptides in glioma and oligomer channel functional analysis using in silico approaches. PLoS One, 2021, 16(3): e0248634. DOI:10.1371/journal.pone.0248634
|
[78] |
Dai J, Su YZ, Zhong SY, et al. Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther, 2020, 5(1): 145. DOI:10.1038/s41392-020-00261-0
|
[79] |
Huang NN, Li FY, Zhang ML, et al. An upstream open reading frame in phosphatase and tensin homolog encodes a circuit breaker of lactate metabolism. Cell Metab, 2021, 33(1): 128-144.e9. DOI:10.1016/j.cmet.2020.12.008
|
[80] |
Guo ZW, Meng Y, Zhai XM, et al. Translated long non-coding ribonucleic acid ZFAS1 promotes cancer cell migration by elevating reactive oxygen species production in hepatocellular carcinoma. Front Genet, 2019, 10: 1111. DOI:10.3389/fgene.2019.01111
|
[81] |
Xu WL, Deng B, Lin PH, et al. Ribosome profiling analysis identified a KRAS-interacting microprotein that represses oncogenic signaling in hepatocellular carcinoma cells. Sci China Life Sci, 2020, 63(4): 529-542. DOI:10.1007/s11427-019-9580-5
|
[82] |
Lun YZ, Pan ZP, Liu SN, et al. The peptide encoded by a novel putative lncRNA HBVPTPAP inducing the apoptosis of hepatocellular carcinoma cells by modulating JAK/STAT signaling pathways. Virus Res, 2020, 287: 198104. DOI:10.1016/j.virusres.2020.198104
|
[83] |
Zhang ML, Zhao K, Xu XP, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun, 2018, 9(1): 4475. DOI:10.1038/s41467-018-06862-2
|
[84] |
Zheng LH, Li LZ, Xie J, et al. Six novel biomarkers for diagnosis and prognosis of esophageal squamous cell carcinoma: validated by scRNA-seq and qPCR. J Cancer, 2021, 12(3): 899-911. DOI:10.7150/jca.50443
|
[85] |
Wu SQ, Zhang LY, Deng JQ, et al. A novel micropeptide encoded by Y-linked LINC00278 links cigarette smoking and AR signaling in male esophageal squamous cell carcinoma. Cancer Res, 2020, 80(13): 2790-2803. DOI:10.1158/0008-5472.CAN-19-3440
|
[86] |
Banday AR, Papenberg BW, Prokunina-Olsson L. When the smoke clears m6A from a Y chromosome-linked lncRNA, men get an increased risk of cancer. Cancer Res, 2020, 80(13): 2718-2719. DOI:10.1158/0008-5472.CAN-20-0961
|
[87] |
Lu SH, Zhang J, Lian XL, et al. A hidden human proteome encoded by 'non-coding' genes. Nucleic Acids Res, 2019, 47(15): 8111-8125. DOI:10.1093/nar/gkz646
|
[88] |
Li MW, Li X, Zhang YN, et al. Micropeptide MIAC inhibits HNSCC progression by interacting with aquaporin 2. J Am Chem Soc, 2020, 142(14): 6708-6716. DOI:10.1021/jacs.0c00706
|
[89] |
De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J, 2016, 6(7): e441. DOI:10.1038/bcj.2016.50
|
[90] |
Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ, 2021, n2026. DOI:10.1136/bmj.n2026
|
[91] |
Sun LY, Wang WT, Han C, et al. The oncomicropeptide APPLE promotes hematopoietic malignancy by enhancing translation initiation. Mol Cell, 2021, 81(21): 4493-4508.e9. DOI:10.1016/j.molcel.2021.08.033
|
[92] |
Hu L, Wang J, Huang HJ, et al. YTHDF1 regulates pulmonary hypertension through translational control of MAGED1. Am J Respir Crit Care Med, 2021, 203(9): 1158-1172. DOI:10.1164/rccm.202009-3419OC
|
[93] |
Liu Y, Zhang HY, Li YY, et al. Long noncoding RNA Rps4l mediates the proliferation of hypoxic pulmonary artery smooth muscle cells. Hypertension, 2020, 76(4): 1124-1133. DOI:10.1161/HYPERTENSIONAHA.120.14644
|
[94] |
Li YY, Zhang JT, Sun HL, et al. Lnc-Rps4l-encoded peptide RPS4XL regulates RPS6 phosphorylation and inhibits the proliferation of PASMCs caused by hypoxia. Mol Ther, 2021, 29(4): 1411-1424. DOI:10.1016/j.ymthe.2021.01.005
|
[95] |
Piamsiri C, Maneechote C, Siri-Angkul N, et al. Targeting necroptosis as therapeutic potential in chronic myocardial infarction. J Biomed Sci, 2021, 28(1): 25. DOI:10.1186/s12929-021-00722-w
|
[96] |
Spencer HL, Sanders R, Boulberdaa M, et al. The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function. Cardiovasc Res, 2020, 116(12): 1981-1994. DOI:10.1093/cvr/cvaa008
|
[97] |
Spiroski AM, Sanders R, Meloni M, et al. The influence of the LINC00961/SPAAR locus loss on murine development, myocardial dynamics, and cardiac response to myocardial infarction. Int J Mol Sci, 2021, 22(2): 969. DOI:10.3390/ijms22020969
|
[98] |
Savard J, Marques-Souza H, Aranda M, et al. A segmentation gene in Tribolium produces a polycistronic mRNA that codes for multiple conserved peptides. Cell, 2006, 126(3): 559-569. DOI:10.1016/j.cell.2006.05.053
|
[99] |
Kondo T, Plaza S, Zanet J, et al. Small peptides switch the transcriptional activity of shavenbaby during Drosophila embryogenesis. Science, 2010, 329(5989): 336-339. DOI:10.1126/science.1188158
|
[100] |
Ray S, Rosenberg MI, Chanut-Delalande H, et al. The mlpt/Ubr3/Svb module comprises an ancient developmental switch for embryonic patterning. eLife, 2019, 8: e39748. DOI:10.7554/eLife.39748
|
[101] |
Mise S, Matsumoto A, Shimada K, et al. Kastor and polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis. Nat Commun, 2022, 13(1): 1071. DOI:10.1038/s41467-022-28677-y
|
[102] |
Ye MJ, Zhang JJ, Wei M, et al. Emerging role of long noncoding RNA-encoded micropeptides in cancer. Cancer Cell Int, 2020, 20: 506. DOI:10.1186/s12935-020-01589-x
|
[103] |
Budamgunta H, Olexiouk V, Luyten W, et al. Comprehensive peptide analysis of mouse brain striatum identifies novel sORF-encoded polypeptides. Proteomics, 2018, 18(10): e1700218. DOI:10.1002/pmic.201700218
|