bims-micpro 2025-11-30 papers

bims-micpro

Biomed News

on Discovery and characterization of microproteins

Issue of 2025–11–30
nine papers selected by
Thomas Farid Martínez, University of California, Irvine

Simple molecules make difference: short peptides play a novel role in slowing senescence.
Translation regulation of ATF4 by the termination complex Hbs1-Pelo is required for visual system development and function.
Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila.
Start Right to End Right: Authentic Open Reading Frame Selection Matters for Nonsense-Mediated Decay Target Identification.
Bioactive Plasmid- and Phage-Encoded Antimicrobial Peptides (AMPs) in the Human Gut: A Metatranscriptome-Virome Profiling Reveals Exploratory Links to Metabolic Human Diseases.
Microprotein PLUM encoded by Lin28b uORF is a cytoplasmic determinant of pluripotency and embryonic development.
The novel endogenous micropeptide XLH-36 binds Gemin4 to promote triple-negative breast cancer metastasis.
De novo genes: current status and future goals.
PeanutOmics: A comprehensive platform with integrative multi-omics atlas for peanut research.

NPJ Aging. 2025 Nov 26.

Simple molecules make difference: short peptides play a novel role in slowing senescence.

Ya Li, Xiangzhan Zhu, Pengya Feng, Chunjing Qiu, Xia Xue, Xiangdong Sun.

Aging studies have entered a transformative era with the discovery and application of short peptides as regulators of senescence. These short peptides are encoded by small open reading frames in nuclear, mitochondrial, and viral genomes. Unlike non-coding RNAs, short peptides are evolutionarily conserved and play a role in ameliorating decline of cellular function. It has now been recognized involved in nearly all biological processes, including diseases and senescence, however, the mechanisms behind it are complicated and largely unexplored. This review aims to summarize the evidence that short peptides slow senescence by targeting interactions with core aging hallmarks in animals. The cross-species studies were reviewed from nematodes to mammals, in which short peptides can modulate the aging-related targets precisely, such as sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pumps and Bcl-2-associated X protein complexes. In parallel, the disorder of these short peptides accelerates age-related pathologies, while therapeutic administration extends healthspan in different animal models. Short peptides achieve disproportionate biological functions while challenges remain in peptide detection, delivery, and mechanistic decoding, yet engineered variants and gene therapies hold promise for clinical translation. By bridging molecular simplicity with systemic resilience, short peptides redefine strategies for healthy aging.

DOI: https://doi.org/10.1038/s41514-025-00292-3
bioRxiv. 2025 Oct 08. pii: 2025.10.08.681214. [Epub ahead of print]

Translation regulation of ATF4 by the termination complex Hbs1-Pelo is required for visual system development and function.

Katherine Querry, Inês Lago-Baldaia, Narayanan Nampoothiri V P, Christopher Garbark, Abby J Carney, Vilaiwan M Fernandes, Deepika Vasudevan.

Inherited retinal diseases are a class of genetically heterogenous disorders characterized by mutations in genes required for retinal function, resulting in progressive loss of vision in human patients. One such deletion mutation in the translation termination factor, HBS1L, results in a suite of developmental anomalies in human patients, including progressive vision loss defects. HBS1L, and its interaction partner Pelota (Pelo), are required for recycling stalled ribosomes on mRNAs, but the specific mRNA target causative of vision defects seen with HBS1L deletion remains unknown. Further, the specific cell types in the visual system that require HBS1L for proper development and function are also unknown. Here, we discover that loss of the Drosophila HBS1L homolog, Hbs1 , results in reduced expression of the stress responsive Activating Transcription Factor 4 (ATF4) which is encoded by an mRNA containing multiple upstream open reading frames (uORFs) in its 5' leader. We corroborate these results in cultured human cells, where we find that HBS1L and Pelo promote translation reinitiation at the ATF4 ORF by facilitating proper translation termination at the preceding uORFs. Like human HBS1L deficiency patients, loss of function Drosophila mutants for Hbs1 , pelo , and ATF4 show vision defects as measured by electroretinograms (ERG). Depleting Hbs1 in lamina neurons replicated the ERG defects seen in Hbs1 mutants, suggesting that Hbs1-Pelo is required for proper lamina neuron function. Further confocal analysis of Hbs1 mutants revealed 'vacuolization' defects in the lamina layer, which are indicative of defective synapse formation between lamina neurons and photoreceptors. Strikingly, restoring ATF4 expression in the lamina partially rescued ERG defects in Hbs1 mutants, indicating that ATF4 is likely a relevant mRNA target regulated by Hbs1-Pelo in these cells. Together, our data support a model wherein Hbs1-Pelo mediated translation regulation of ATF4 in lamina neurons underlies the inherited retinal disease caused by HBS1L deletion.

DOI: https://doi.org/10.1101/2025.10.08.681214
Nat Commun. 2025 Nov 26.

Microproteins Simba1 and Simba2 activate Wingless signaling during the reactivation of neural stem cells in Drosophila.

Jiaen Lin, Qiannan Deng, Yang Gao, Ye Sing Tan, Zheng Zhong, Lay Keng Angie Tan, Boon Ooi Patrick Tan, David M Virshup, Justin A Bosch, Norbert Perrimon, Hongyan Wang.

The ability of neural stem cells (NSCs) to switch between quiescent and proliferative states is fundamental for adult neurogenesis and regeneration. Microproteins or short open reading frame (sORF)-encoded peptides (SEPs), are highly abundant yet largely understudied, and their role in brain development remains unclear. Here, we demonstrate that two evolutionarily-conserved microprotein paralogs, Simba1 and Simba2, encoded by sORFs CG15715 and CG18081, respectively, govern the reactivation of Drosophila quiescent NSCs. Both Simba1 and Simba2 function in NSCs and Blood-Brain-Barrier (BBB) glial cells to promote NSC reactivation. Mechanistically, Simba1 and Simba2 act as transcription factors activating the WNT/Wingless signalling pathway during NSC reactivation. We uncover a critical role of Wg signalling molecules in promoting NSC reactivation and the translocation of Wingless from BBB glia to NSCs. Our findings reveal a role for microproteins Simba1/2 in regulating NSC reactivation through Wg signalling. Moreover, our bioinformatic analysis and luciferase assay suggest that ZNF706, the human ortholog of Simba1/2, is required for WNT signaling activation in human cells. The conserved function of Simba1/2/ZNF706 in activating WNT/Wg signalling in Drosophila and humans suggests that this new regulatory paradigm may be applicable to broader cellular processes and disease conditions.

DOI: https://doi.org/10.1038/s41467-025-66727-3
Genes (Basel). 2025 Nov 01. pii: 1297. [Epub ahead of print]16(11):

Start Right to End Right: Authentic Open Reading Frame Selection Matters for Nonsense-Mediated Decay Target Identification.

Mojtaba Bagherian, Georgina Harris, Pratosh Sathishkumar, James P B Lloyd.

   BACKGROUNDS: Accurate annotation of open reading frames (ORFs) is fundamental for understanding gene function and post-transcriptional regulation. A critical but often overlooked aspect of transcriptome annotation is the selection of authentic translation start sites. Many genome annotation pipelines identify the longest possible ORF in alternatively spliced transcripts, using internal methionine codons as putative start sites. However, this computational approach ignores the biological reality that ribosomes select start codons based on sequence context, not ORF length.
METHODS: Here, we demonstrate that this practice leads to systematic misannotation of nonsense-mediated decay (NMD) targets in the Arabidopsis thaliana Araport11 reference transcriptome. Using TranSuite software to identify authentic start codons, we reanalyzed transcriptomic data from an NMD-deficient mutant.
RESULTS: We found that correct ORF annotation more than doubles the number of identifiable NMD targets with premature termination codons followed by downstream exon junctions, from 203 to 426 transcripts. Furthermore, we show that incorrect ORF annotations can lead to erroneous protein structure predictions, potentially introducing computational artefacts into protein databases.
CONCLUSIONS: Our findings underscore the importance of biologically informed ORF annotation for accurate assessment of post-transcriptional regulation and proteome prediction, with implications for all eukaryotic genome annotation projects.

Keywords:  NMD; ORF; alternative splicing; genome annotation; genomes; genomics

DOI:  https://doi.org/10.3390/genes16111297
Microb Ecol. 2025 Nov 28.

Bioactive Plasmid- and Phage-Encoded Antimicrobial Peptides (AMPs) in the Human Gut: A Metatranscriptome-Virome Profiling Reveals Exploratory Links to Metabolic Human Diseases.

Luigui Gallardo-Becerra, Fernanda Cornejo-Granados, Shirley Bikel, Iván Arenas, Gamaliel López-Leal, Carolina Alvarado-Gonzalez, Filiberto Sánchez-López, Rubiceli Manzo, Gerardo Corzo, Gerardo P Espino-Solis, Samuel Canizales-Quinteros, Adrian Ochoa-Leyva.

  Microbe-derived antimicrobial peptides (AMPs) can shape gut community structure; however, their contribution to disease-associated dysbiosis remains poorly understood. We assembled fecal metatranscriptomes from individuals with normal weight (NW), obesity (O), and obesity with metabolic syndrome (OMS), yielding 51,087 non-human transcripts. We screened 1,095 small open reading frames (smORFs) using AMP-prediction algorithms combined with stringent post-hoc bioinformatics filters identifying 51 high-confidence AMP candidates. Most matched bacterial homologs, predominantly Faecalibacterium prausnitzii, while eight mapped to plasmids or bacteriophages. Differential expression identified two and four AMPs overexpressed in O and OMS, respectively. Two of them were originated from chromosomes, three from phages, and one from plasmid. Notably, the over-expression of these AMPs was negatively correlated with healthy-associated bacteria and positively correlated with obesity-enriched taxa. Furthermore, these AMPs were broadly detectable across 372 external gut metatranscriptomes (prevalence up to 94% of the samples) indicating conservation within the human gut microbiome and highlighting mobile elements as an overlooked reservoir of transcriptionally active AMPs. Using DNA virome sequencing and prophage analyses, we suggested phage origin of the transcribed AMPs. We further synthesized a phage-encoded AMP (AMP-3020), demonstrating broad-spectrum activity against Gram-positive and Gram-negative bacteria, without detectable cytotoxicity toward human immune T cells. This supports the idea that phages could encode functional AMPs capable of shaping gut community structure by suppressing diverse bacteria without harming host immune cells. Our gut metatranscriptome-virome profiling revealed a conservative core of actively transcribed, plasmid- and phage-encoded AMPs with exploratory associations to obesity/MetS. These findings support mobile-element AMPs as candidate ecological regulators and motivate validation in larger cohorts and mechanistic models.

Keywords:  AMPs; Antimicrobial peptides; Metatranscriptome; Phages; Plasmid; Virome

DOI:  https://doi.org/10.1007/s00248-025-02620-2
Nat Commun. 2025 Nov 26. 16(1): 10324

Microprotein PLUM encoded by Lin28b uORF is a cytoplasmic determinant of pluripotency and embryonic development.

Zhihong Hao, Yi Wu, Yile Huang, Maolei Zhang, Yang Liu, Yueqiao Li, Wenxin Li, Zifeng Ruan, Jian Zhang, Yingzhe Ding, Linpeng Li, Guangsuo Xing, Zichao Liu, Yanshuang Zhou, Qi Wang, Keshi Chen, Wuming Wang, Gang Lu, Dajiang Qin, Wai-Yee Chan, Xingguo Liu.

The crosstalk between translation and metabolism is fundamental for cellular plasticity. While most studies focus on translation within canonical coding regions, the roles of non-canonical open reading frames (ORFs) in metabolic regulation and early development remain unclear. Here, we show that selective translation of an upstream ORF in the 5' untranslated region (UTR) of Lin28b produces an 85-amino acid microprotein, PLUM (pluripotency-associated Lin28b uORF-encoded microprotein). Depletion of PLUM leads to deterministic and synchronized (near 100%) induction of naïve pluripotency and causes embryo implantation defects in vivo. Mechanistically, PLUM depletion dissolves L1td1 condensates and enhances L1td1 binding to pluripotency mRNAs such as Tfcp2l1 and Zfp42, stabilizing them and promoting coordinated gene activation. Concurrently, PLUM loss disrupts P-bodies enriched with a subset of nuclear-encoded mitochondrial mRNA, potentially preventing their degradation. Together, these alterations trigger an early burst of mitochondrial oxidative phosphorylation and synchronized naïve gene expression, accelerating acquisition of the naïve state. Our study identifies the novel uORF-encoded microprotein PLUM as a pluripotency determinant integrating RNA regulation and metabolic remodeling.

DOI: https://doi.org/10.1038/s41467-025-66297-4
Oncogene. 2025 Nov 29.

The novel endogenous micropeptide XLH-36 binds Gemin4 to promote triple-negative breast cancer metastasis.

Mengwei Li, Wenwei Xie, Kexin Hu, Tiantian Li, Xin Li, Li Shun, Xiaowei Xu, Junhui Chen, Hanmei Xu.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype. The 5-year overall survival rate of TNBC patients is 77%, but once cancer metastasis occurs, this rate drops to 12%. To date, the discovery of biomarkers associated with TNBC metastasis remains a major challenge. In this study, we identified a novel translated product, XLH-36 micropeptide, encoded by lncRNA (long non-coding RNA) C5orf66-AS1, which acts as an "oncogenic driver" in TNBC. Through conservation analyses across 101 species, we found that XLH-36 is highly conserved in humans and primates. Analysis of RNA-seq data from 1295 breast cancer patients, including 165 TNBC patients from different cohorts, revealed significantly elevated XLH-36 expression levels in breast cancer and TNBC. Specifically, TNBC patients with low C5orf66-AS1 (encoding XLH-36) expression demonstrated a 20% higher overall survival rate compared to those with high C5orf66-AS1 expression over a 50-month follow-up. XLH-36 knockout inhibited the growth and metastasis of TNBC xenografts in mice. Furthermore, we found that XLH-36 directly binds Gemin4, causing it to remain in the cytoplasm and preventing it from carrying out its role in promoting S100A4 mRNA splicing in the nucleus. This leads to a compensatory increase in ICAM1 levels, ultimately resulting in the promotion of epithelial-to-mesenchymal transition (EMT) in TNBC cells and an increase in tumor metastasis. In summary, our findings highlight the crucial role of XLH-36 in TNBC metastasis, which could be exploited in the development of therapeutic and diagnostic strategies for TNBC patients.

DOI: https://doi.org/10.1038/s41388-025-03621-8
Genome Biol Evol. 2025 Nov 28. pii: evaf230. [Epub ahead of print]

De novo genes: current status and future goals.

Claudio Casola, Victor Luria, Nikolaos Vakirlis, Li Zhao.

  The recent Society for Molecular Biology and Evolution Satellite Meeting on De Novo Gene Birth, hosted at Texas A&M University on November 6-9, 2023, represented the first-ever opportunity for scientists studying the evolution and biology of de novo genes to gather through a dedicated meeting and discuss about groundbreaking discoveries in this emerging and exciting field of gene evolution. In this perspective, we discuss recent advances and major open questions in de novo gene emergence and evolution that were presented at the SMBE satellite meeting, as well as some of the key recent findings published before or since the conference. These key themes include de novo gene identification, function and evolution, what we are learning about de novo genes from experimental analyses of random peptides, de novo gene birth and microproteins, and the role of de novo genes in human disease.

Keywords:  comparative genomics; gene evolution; genome evolution; microproteins; random peptides; ribosome profiling

DOI:  https://doi.org/10.1093/gbe/evaf230
Plant Commun. 2025 Nov 22. pii: S2590-3462(25)00384-0. [Epub ahead of print] 101622

PeanutOmics: A comprehensive platform with integrative multi-omics atlas for peanut research.

Hongzhang Xue, Kunkun Zhao, Xiaorui Dong, Qian Ma, SaSa Hu, Zenghui Cao, Yang Shu, Yanzhe Li, Xiaoxiang Huang, Kai Zhao, Ding Qiu, Wenguang Shao, Rui Ren, Zhongfeng Li, Fangping Gong, Xingli Ma, Chaochun Wei, Dongmei Yin.

  Peanut (Arachis hypogaea L.) is an economically important legume crops, yet a comprehensive understanding of its gene expression dynamics across developmental stages remains limited. To address this, we constructed a multi-omics atlas spanning transcriptomic, proteomic, and metabolomic profiles across 22 primary vegetative and reproductive tissues. We identified 53,030 expressed genes at the transcript level, 12,826 with protein evidence, and 2,035 metabolites. Among these, 2,147 genes encoded novel proteins and 274 produced microproteins. Functional analysis identified WDR13, TANGO, RPP13, DEF3, SLR1-BP, and SLE2 as key genes with roles in development and stress response. Co-expression analysis grouped genes into 24 modules, many showing tissue-specific expression. Pathway enrichment and correlation network analysis highlighted the critical roles of IAA and ARF gene families in hormone signaling and cell growth, particularly in peg development. To support data accessibility and downstream research, we developed PeanutOmics (https://cgm.sjtu.edu.cn/PeanutOmics), a user-friendly platform integrating multi-omics datasets with advanced analytical tools. This atlas offers a valuable resource for understanding gene and metabolite regulation in peanut and lays the groundwork for advanced molecular breeding and improved crop productivity.

Keywords:  Database; Metabolomics; Multi-omics; Peanut; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.xplc.2025.101622