MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid β-Oxidation

Makarewich, Catherine A.; Baskin, Kedryn K.; Munir, Amir Z.; Bezprozvannaya, Svetlana; Sharma, Gaurav; Khemtong, Chalermchai; Shah, Akansha M.; McAnally, John; Malloy, Craig R.; Szweda, Luke I.; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1016/j.celrep.2018.05.058

Cited by 127 publications

(142 citation statements)

References 34 publications

(44 reference statements)

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“…Recent studies have discovered that a few lncRNAs harbor small open reading frames (sORFs) that encode sORF-encoded peptides (SEPs) or micropeptides [12][13][14][15][16][17][18][19][20] . We hypothesized that there are additional transcripts currently annotated as lncRNAs that may encode micropeptides.…”

Section: An Incrna Tunar Encodes a Conserved 48-amino-acid Micropepmentioning

confidence: 99%

“…LncRNAs regulate key biological processes through regulation of transcriptional activation, heterochromatin formation, interaction with miRNAs and other mechanisms 39,40 . However, recent studies have revealed that some transcripts identified as IncRNAs actually do contain sORFs that encode micropeptide (microprotein) [12][13][14][15][16][17][18][19][20] . In this study, we applied two computational programs PhyloCSF and RNAcode to prioritize the search for additional micropeptide encoding lncRNAs.…”

Section: Disscusionmentioning

confidence: 99%

“…In total, we identified 225 putative sORFs that encode micropeptides from human lncRNAs. With our computational discovery pipeline, all 12 lncRNAs that were recently identified as encoding micropeptides [12][13][14][15][16][17][18][19][20] were recovered in our micropeptide computational discovery pipeline ( Fig. 1B).…”

Section: Disscusionmentioning

confidence: 99%

“…This filtering strategy dramatically reduces the likelihood of false-positive detection, but may also result in some genes that contain small open reading frames (sORFs) being mis-annotated as lncRNAs 11 . Indeed, recent studies have revealed that some of IncRNAs do contain sORFs that encode micropeptides (or microprotein, protein less than 100 amino acids in length) [12][13][14][15][16][17][18][19][20] . Micropeptides can act as modulators for larger protein complexes such as the sarco/endoplasmic reticulum Ca-ATPase (SERCA).In addition, micropeptides can also function independently by serving as ligands for receptors 21 , or scaffolds for protein-protein interactions 17 .…”

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confidence: 99%

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A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β-cells

Shao

Qian

et al. 2020

Preprint

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Micropeptides(microproteins) encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) 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 human pancreas. We experimentally verified one such micropeptide encoded by the β-celland neural cell-enriched lncRNA TUNAR (TUNA / HI-LNC78 / LINC00617). We named this highly conserved 48-amino-acid micropeptide Beta cell-and Neural cell-regulin (BNLN). BNLN contains a singlepass transmembrane domain. In pancreatic β-cells, BNLN mainly localized at the endoplasmic reticulum.Overexpression of BNLN lowered ER calcium levels, increased cytosolic calcium levels, and maintained ER homeostasis in response to high glucose challenge. To determine the physiological and pathological roles of BNLN, we assessed the BNLN expression in islets from mice fed with a high-fat diet and a regular diet, and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN elevated glucose-stimulated insulin secretion in INS-1 cells. Lastly, BNLN overexpression 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 function and provides a foundation on which to perform future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes. Abbreviations:ATF6: activating transcription factor-6; BNLN: beta cell and neuron regulin; Cre: Cre recombinase; DIO: diet-induced obesity; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Glc: glucose; HFD: high-fat diet; IncRNA: long noncoding RNA; RD: regular diet; sORF: small open reading frame; T2D: type 2 diabetes; TUNAR: TCL1 Upstream Neural Differentiation-Associated RNA. INTRODUCTION:Large-scale projects such as ENCODE and FANTOM have found thousands of long noncoding RNAs (lncRNAs) in the human genome 1-4 . lncRNAs play an essential role in regulating islet function in health and diseases including diabetes 5 . It has been demonstrated that lncRNAs are key components of the islet regulatome, with more than 1000 lncRNAs identified in human islets and mouse β-cells 6,7 . These lncRNAs play critical roles in islet and β-cell survival, cell development, and physiological function through regulation of the islet transcriptome 5-7 . Of note, a genome-wide association study that examined T2D susceptibility loci demonstrated that dysregulation of IncRNAs is involved in pancreatic pathologies in humans 6 . In addition, dysregulation of lncRNAs has been implicated in diabetes complications, such as diabetic nephropathy and retinopathy 5,8 . Recently, several circulating lncRNAs have been identified as biomarkers of diabetes and diabetic complications 9,10 . However, although much knowledge has accumulated correlating d...

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Section: An Incrna Tunar Encodes a Conserved 48-amino-acid Micropepmentioning

confidence: 99%

Section: Disscusionmentioning

confidence: 99%

Section: Disscusionmentioning

confidence: 99%

mentioning

confidence: 99%

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A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β-cells

Shao

Qian

et al. 2020

Preprint

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“…Additionally, micropeptide regulator of b-oxidation (MOXI), a 56-aa microprotein encoded by muscleenriched long non-coding RNAs (lncRNA) LINC00116, was found to be located in mitochondrion and enhance fatty acid β-oxidation [15,16]. By applying our method to several expression datasets of skeletal muscle tissues, we successfully predicted not only its cellular localization, but also the enrichment of cellular respiratory pathways such as oxidative phosphorylation (Fig.…”

Section: Prediction Of Microprotein Function Based On Expression Simimentioning

confidence: 99%

smORFunction: A Tool for Predicting Functions of Small Open Reading Frames and Microproteins

Cui

2020

Preprint

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Background Small open reading frame (smORF) is open reading frame with a length of less than 100 codons. Microproteins, translated from smORFs, have been found to participate in a variety of biological processes such as muscle formation and contraction, cell proliferation, and immune activation. Although previous studies have collected and annotated a large abundance of smORFs, functions of the vast majority of smORFs are still unknown. It is thus increasingly important to develop computational methods to annotate the functions of these smORFs. Results In this study, we collected 617,462 unique smORFs from three studies. The expression of smORF RNAs was estimated by reannotated microarray probes. Using a speed-optimized correlation algorism, the functions of smORFs were predicted by their correlated genes with known functional annotations. After applying our method to 5 known microproteins from literatures, our method successfully predicted their functions. Further validation from the UniProt database showed that at least one function of 202 out of 270 microproteins was predicted. Conclusions We developed a method, smORFunction, to provide function predictions of smORFs/microproteins in at most 265 models generated from 173 datasets, including 48 tissues/cells, 82 diseases (and normal). The tool can be available at http://www.cuilab.cn/smorfunction.

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LINC00998‐encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level

et al. 2022

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The biological functions of short open reading frame (sORF)‐encoded micropeptides remain largely unknown. Here, we report that LINC00998 , a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N‐nitrosodiethylamine‐induced hepatoma. Overexpression of the 5′UTR‐sORF sequence of LINC00998 , encoding wild‐type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single‐base deletion. Gain‐ and loss‐of‐function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated‐Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.

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MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid β-Oxidation

Cited by 127 publications

References 34 publications

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

smORFunction: A Tool for Predicting Functions of Small Open Reading Frames and Microproteins

LINC00998‐encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level

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