A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β cells.
A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β cells.
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DOI：
10.1016/j.omtn.2021.06.027
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Cao H
中科院分区：
文献类型：
--
作者：
Li M;Shao F;Qian Q;Yu W;Zhang Z;Chen B;Su D;Guo Y;Phan AV;Song LS;Stephens SB;Sebag J;Imai Y;Yang L;Cao H
由先前注释为长链非编码RNA（lncRNA）的转录本编码的微肽（微蛋白）正在成为健康和疾病基本生物过程的重要介质。在这里，我们应用了两种计算工具来识别由人类胰腺中表达的lncRNA编码的推定的微肽。我们通过实验验证了一种由β细胞和神经细胞富集的lncRNA TCL 1上游神经分化相关RNA（TUNAR，也称为TUNA，HI-LNC 78或LINC 00617）编码的此类微肽。我们将这种高度保守的48个氨基酸的微肽命名为β细胞和神经细胞调节素（BNLN）。BNLN含有一个单次跨膜结构域，定位于胰腺β细胞的内质网（ER）。BNLN的过表达降低了ER钙水平，维持了ER稳态，并提高了胰腺β细胞中葡萄糖刺激的胰岛素分泌。我们进一步评估了高脂饮食和普通饮食小鼠胰岛中BNLN的表达，发现BNLN被饮食诱导的肥胖症（DIO）抑制。相反，BNLN的过度表达增强了瘦小鼠和肥胖小鼠以及人类胰岛中的胰岛素分泌。总之，我们的研究提供了第一个证据，表明lncRNA编码的微肽在胰腺β细胞功能中起着关键作用，并为未来全面分析微肽功能和对糖尿病的病理生理影响提供了基础。在这项研究中，我们确定了一个胰岛lncRNA，TUNEL，含有一个sORF编码的微肽BNLN。我们进一步证明了BNLN调节健康和疾病中胰腺β细胞中的胰岛素分泌。我们的研究提供了重要的见解的分子机制，基础微调葡萄糖诱导的胰岛素分泌的lncRNA的翻译功能。
Micropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNAs (lncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here, we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a β cell- and neural cell-enriched lncRNA TCL1 Upstream Neural Differentiation-Associated RNA (TUNAR, also known as TUNA, HI-LNC78, or LINC00617). We named this highly conserved 48-amino-acid micropeptide beta cell- and neural cell-regulin (BNLN). BNLN contains a single-pass transmembrane domain and localizes at the endoplasmic reticulum (ER) in pancreatic β cells. Overexpression of BNLN lowered ER calcium levels, maintained ER homeostasis, and elevated glucose-stimulated insulin secretion in pancreatic β cells. We further assessed the BNLN expression in islets from mice fed a high-fat diet and a regular diet and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β cell functions and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes. In this study, we identified one islet lncRNA, TUNAR, contains a sORF encoding for micropeptide BNLN. We further demonstrated that BNLN regulates insulin secretion in the pancreatic β cells in health and diseases. Our study provides important insights into the molecular mechanisms that underlie the fine-tuning of glucose-induced insulin secretion by translational function of lncRNA.
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影响因子：
29
作者：
Akerman I;Tu Z;Beucher A;Rolando DMY;Sauty-Colace C;Benazra M;Nakic N;Yang J;Wang H;Pasquali L;Moran I;Garcia-Hurtado J;Castro N;Gonzalez-Franco R;Stewart AF;Bonner C;Piemonti L;Berney T;Groop L;Kerr-Conte J;Pattou F;Argmann C;Schadt E;Ravassard P;Ferrer J
通讯作者：
Ferrer J
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.1113319109
发表时间：
2012-03-13
影响因子：
11.1
作者：
Beigi, Farideh;Gonzalez, Daniel R.;Hare, Joshua M.
通讯作者：
Hare, Joshua M.
影响因子：
4
作者：
Berridge, MJ
通讯作者：
Berridge, MJ
DOI：
10.1016/j.bbacli.2015.09.001
发表时间：
2015-12
期刊：
BBA clinical
影响因子：
--
作者：
Carter G;Miladinovic B;Patel AA;Deland L;Mastorides S;Patel NA
通讯作者：
Patel NA