bims-micpro 2026-05-10 papers

Nature. 2026 May 06.

Expanding the human proteome with microproteins and peptideins.

Eric W Deutsch, Leron W Kok, Jonathan M Mudge, Cristian F Valls, Irwin Jungreis, Jorge Ruiz-Orera, Zhi Sun, Ulrike Kusebauch, Ivo Fierro-Monti, Jennifer G Abelin, M Mar Alba, Julie L Aspden, Sreejan Bandyopadhyay, Kaushik Banerjee, Pavel V Baranov, Ariel A Bazzini, Francis Bourassa, Elspeth A Bruford, Lorenzo Calviello, Steven A Carr, Anne-Ruxandra Carvunis, Sonia Chothani, Jim Clauwaert, Kellie Dean, Pouya Faridi, Adam Frankish, Amy Goodale, Thomas Green, Norbert Hubner, Nicholas T Ingolia, Manolis Kellis, Michele Magrane, Maria Jesus Martin, Thomas F Martinez, Gerben Menschaert, Uwe Ohler, Sandra Orchard, Alisa Potter, Owen J L Rackham, Matthew G Rees, David E Root, Jennifer A Roth, Xavier Roucou, Fernando J Sialana, Sarah A Slavoff, Michał I Świrski, Jack A S Tierney, Félix-Antoine Trifiro, Eivind Valen, Valeriia Vasylieva, Aaron Wacholder, Shengbo Wang, Li Wang, Jonathan S Weissman, Wei Wu, Zhi Xie, Jyoti S Choudhary, Michal Bassani-Sternberg, Juan Antonio Vizcaíno, Nicola Ternette, Marie A Brunet, Robert L Moritz, John R Prensner, Sebastiaan van Heesch.

A major scientific drive is to characterize the protein-coding genome, which is a primary basis for studying human health. But the fundamental question remains of what has been missed in previous analyses. Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states1-3, with major implications for biomedical science. However, a key gap in knowledge has been which ncORFs produce small microproteins or alternative protein molecules that contribute to the human proteome. Here we report the collaborative efforts of the TransCODE Consortium4 to produce a consensus landscape of protein-level evidence for ncORFs. We show that about 25% of a set of 7,264 ncORFs gives rise to detectable peptides in a large-scale analysis of 95,520 proteomics experiments. We develop an annotation framework for ncORF-encoded microproteins as human proteins and codify the new conceptual model of 'peptideins' as microproteins that have indeterminate potential as functional proteins. To probe the biological implications of peptideins, we create an evolutionary analysis approach, termed ORF relative branch length (ORBL), and determine that evolutionary constraint is common and associates with observation of ncORF-derived peptides. We then characterize a pan-essential cellular phenotype for one peptidein from the OLMALINC long non-coding RNA. Overall, we generate public research tools supported by GENCODE and PeptideAtlas and advance biomedical discovery for understudied components of the human proteome.

DOI: https://doi.org/10.1038/s41586-026-10459-x

Nucleic Acids Res. 2026 May 05. pii: gkag427. [Epub ahead of print]54(9):

Suppression of upstream ORF translation is not a widespread mechanism of translational stimulation by yeast helicase Ded1.

Rakesh Kumar, Gemma May, Neelam Dabas Sen, C Joel McManus, Alan G Hinnebusch.

Ded1 is an essential DEAD-box helicase in yeast that broadly stimulates translation initiation and is critical for messenger RNAs (mRNAs) with structured 5' untranslated regions (UTRs). We have evaluated the proposal that Ded1 stimulates translation primarily by preventing initiation at upstream open-reading-frames (uORFs) associated with stable secondary structures. By Ribo-seq analysis under experimental conditions designed to suppress artifactual 5'UTR translation, we found that reduced translation of the main open-reading-frames (mORFs) in native mRNAs is generally not accompanied by increased 5'UTR translation in ded1 mutant cells, and that the presence of translated uORFs in yeast mRNAs generally does not confer heightened dependence on Ded1 for efficient translation of mORFs. Results from a high-throughput reporter assay examining native 5'UTRs reinforce the importance of Ded1 in initiation from structured 5' UTRs and show that impairing Ded1 has minimal effects on translational repression by uORFs. Our results demonstrate that, in cells growing vegetatively in rich medium, translational stimulation by suppression of inhibitory uORFs is restricted to a minority of Ded1 targets, and that unwinding of 5' UTR secondary structures per se is the principal mechanism for Ded1 stimulation of translation initiation.

DOI: https://doi.org/10.1093/nar/gkag427

EMBO Rep. 2026 May 02.

STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture.

Ruiyang Guo, Yabo Guo, Runguo Shu, Jiajia Qian, Jiawei Wang, Ruobing Li, Ti Qin, Ziyi Wang, Hongtao Tian, Mengchen Wu, Long Zhou, Xiaogang Guo, Shan Zhang.

Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5'UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the SLC35A4 transcript, we show that its 5'UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (SLC35A4 stress response regulating MICOS interactor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of SLC35A4-a Golgi nucleotide sugar transporter-upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of "gene symbiosis" that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.

DOI: https://doi.org/10.1038/s44319-026-00783-8

Cell Death Dis. 2026 May 06.

Micropeptide SCAPEP triggers lung adenocarcinoma tumorigenesis via regulating autophagy by promoting CDK15-mediated phosphorylation of vimentin.

Xuefei Shi, Qiuhui Li, Fengqi Nie, Xuting Xu, Yili Shen, Hui Shen, Kai Chen, Bin Wang, Kaihua Lu, Shunli Dong, Liu Xianghua.

Lung adenocarcinoma is one of the most common forms of lung cancer with a low five-year survival rate. The roles of the novel proteins and peptides encoded by circular RNAs (circRNAs) in cancer are emerging. However, the functions and underlying molecular mechanisms of the peptides that affect lung adenocarcinoma progression are yet to be elucidated. In this study, we characterized a lung-adenocarcinoma-associated small peptide (SCAPEP) encoded by circRNA_0065214 via the IRES element. Tumors with a large diameter, lymphatic metastasis, or advanced stage have high SCAPEP levels. Furthermore, modulation of SCAPEP expression can regulate cell proliferation, metastasis, and autophagy in vitro or in vivo. We found that the up-regulation of methionine synthase reductase (MTRR) by regulating the phosphorylation of vimentin Ser56 in SCAPEP is a key mechanism driving the aggressiveness of SCAPEP -high lung adenocarcinoma. Consistent with these findings, MTRR overexpression reversed the effects of SCAPEP depletion. Altogether, our observations provide novel insights into how oncogenic peptides crosstalk with autophagy and contribute to lung adenocarcinoma tumorigenesis.

DOI: https://doi.org/10.1038/s41419-026-08767-1