bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2026–06–07
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. No Time to Fold: Intrinsically Disordered Microproteins in Action.
  2. Benchmarking reveals the superiority of nucleic acid foundation models in predicting lncRNA coding potential.
  3. Structural Control of NLRP3 Inflammasome Assembly and the Emerging Microprotein Frontier.
  4. Emergence of protein-coding enhancer RNAs in primate evolution.
  5. The translation landscape of ovarian clear cell carcinoma indicates that RBM4 plays a pro-oncogenic role in tumor progression.
  6. Small peptide encoded by MALAT1 aggravates colitis via upregulating GIP expression in enterocyte.
  7. MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases.
  1. Biochemistry. 2026 Jun 05.
    No Time to Fold: Intrinsically Disordered Microproteins in Action.
    Tianyu Chen, Kevin Cao, Thomas F Martinez.
      Advances in genomics, proteomics, and bioinformatics have uncovered the existence of thousands of translated small open reading frames less than 100-150 codons in length that encode microproteins. In addition to their diminutive size, microproteins are also often predicted to be intrinsically disordered based on their enrichment in disordered-promoting amino acids. Microproteins have since been found to regulate diverse cellular processes, including DNA repair, mRNA decay, mitochondrial metabolism, and ribosome biogenesis, among others. While only a small fraction of microproteins have been functionally characterized, many examples have been found to act as regulators of larger proteins and protein complexes in ways similar to annotated intrinsically disordered proteins (IDPs). In this review, we summarize the functions and mechanisms of several disordered microproteins while exploring the approaches used to study their disordered nature, their regulation by post-translational modifications, and potential strategies to therapeutically target them in disease. These examples underscore how investigations of disordered microproteins deepen our understanding of how biological processes are regulated and emphasize how close collaboration between the microprotein and IDP fields can enhance these efforts.
    Keywords:  intrinsically disordered protein; microprotein; small open reading frame
    DOI:  https://doi.org/10.1021/acs.biochem.6c00280
  2. Genome Biol. 2026 Jun 04.
    Benchmarking reveals the superiority of nucleic acid foundation models in predicting lncRNA coding potential.
    Yu Yang, Liping Ren, Juan Feng, Yang Zhang, Tianyuan Liu.
       BACKGROUND: A subset of long noncoding RNAs (lncRNAs) contains short open reading frames and can encode functional micropeptides. However, identifying these coding lncRNAs (codlncRNAs) remains challenging due to weak coding signals, short peptide products, and heterogeneous evidence across databases. Existing computational tools lack unified benchmarks, and the utility of nucleic acid foundation models for this task remains unclear.
    RESULTS: We construct the first multi-species, evidence-stratified benchmark for codlncRNA prediction and systematically characterized codlncRNAs across molecular dimensions. CodlncRNAs consistently exhibited transitional features between mRNAs and untranslated lncRNAs in sequence, structural, and physicochemical properties. Using this benchmark, we evaluate 12 classical tools and 4 foundation models. Classical methods show limited zero-shot performance, whereas RNA-FM, RiNALMo, and DNABERT-2 achieve substantial gains after fine-tuning. Notably, DNABERT-2, trained solely on DNA, performs competitively or even superior to RNA-specific models. An ensemble framework integrating foundation and classical models further improves robustness and has been deployed as an accessible web server.
    CONCLUSIONS: Our study establishes the first benchmark for codlncRNA prediction, delineates their distinctive transitional molecular profile, and supports the utility of nucleic acid foundation models for codlncRNA prediction within the current benchmark scope. Moreover, the proposed framework provides a practical, scalable computational foundation for micropeptide discovery and RNA functional characterization.
    Keywords:  Coding lncRNA prediction; Deep learning; Nucleic acid foundation model; Sequence representation learning
    DOI:  https://doi.org/10.1186/s13059-026-04134-7
  3. FASEB J. 2026 Jun 15. 40(11): e72018
    Structural Control of NLRP3 Inflammasome Assembly and the Emerging Microprotein Frontier.
    Rabab S Hamad, Safwan Abid Al-Hameed Suliman, Mustafa Egla Kadhim, Waseem Ali Hasan, Elsayed A Elmorsy, Eman Hamza, Etedal Ahmed A Ibrahim, Renad M S Mohamed, Hanan Eissa, Alshaimaa A Farrag, Sameh Saber.
      The NLRP3 inflammasome responds to chemically and biologically diverse stimuli, yet growing evidence indicates that this apparent diversity converges on a limited set of structural and spatial licensing steps. Here, we argue that NLRP3 regulation is best understood through an assembly-centered framework rather than as another stimulus-centered catalog of activators. Cryo-electron microscopy (Cryo-EM), biochemical, and cell-biological studies support a model in which NLRP3 is maintained in inactive cage-like assemblies, undergoes nucleotide-dependent conformational rearrangements, engages NEK7, and nucleates ordered supramolecular complexes containing apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We synthesize current evidence for structural licensing, interface-level restraint, subcellular trafficking, phase-separation-linked organization, and post-translational and proteostatic control of NLRP3 assembly. We then examine a less explored question with translational implications: whether peptide-scale regulators, particularly endogenous microproteins, may control defined assembly transitions. Available evidence supports the existence of synthetic peptides that inhibit inflammasome interfaces and of endogenous microproteins that intersect with inflammatory signaling. However, direct evidence that endogenous microproteins act as dedicated interface-mimic inhibitors of NLRP3 assembly remains lacking. This review integrates mature structural models of NLRP3 regulation with the emerging microprotein field while clearly distinguishing established mechanisms from plausible but unproven hypotheses. This perspective defines a mechanistically explicit agenda for future work, including rigorous validation of translated small open reading frames (smORFs), direct interaction mapping to defined NLRP3 surfaces, and quantitative testing of effects on assembly, signaling output, and cellular context.
    Keywords:  NEK7; NLRP3 inflammasome; interface restraint; microproteins; structural licensing; supramolecular assembly
    DOI:  https://doi.org/10.1096/fj.202601817R
  4. Trends Genet. 2026 Jun 05. pii: S0168-9525(26)00134-4. [Epub ahead of print]
    Emergence of protein-coding enhancer RNAs in primate evolution.
    Monica G Valencia Gattas, Ramin Shiekhattar.
      Enhancer RNAs (eRNAs) are short, unstable RNA polymerase II transcripts from active enhancers processed by the Integrator complex. Once considered noncoding, recent work from Vlasov et al. shows that a subset of eRNAs contain open reading frames translated into arginine-rich proteins with exquisite primate specificity, redefining enhancer output and function.
    DOI:  https://doi.org/10.1016/j.tig.2026.05.007
  5. Oncogene. 2026 Jun 05.
    The translation landscape of ovarian clear cell carcinoma indicates that RBM4 plays a pro-oncogenic role in tumor progression.
    Yiying Chen, Dongxu Lu, Yaqi Xing, Jing He, Sumei Zhang, Xiaoxi Wang, Mei Li, Yuming Wang, Yike Gao, Anqi Wang, Kun Zhao, Zixin Zhang, Dan Guo, Shu Wang, Jian Sun.
      Ovarian clear cell carcinoma (OCCC) is a highly aggressive gynecological malignancy characterized by distinct clinicopathological features and resistance to chemotherapy. Despite advances in multi-omics characterization, the translational regulatory landscape of OCCC remains unexplored. Here, we performed ribosome profiling to systematically investigate translation control mechanisms in OCCC. We conducted an integrated analysis of transcriptomic and translatomic data from 22 clinical specimens. This study is the first to analyze translational dysregulation in OCCC at sub-codon resolution using translational group data resources. Integrated analysis identified novel unannotated open reading frames (ORFs) encoding functional micropeptides. Furthermore, we uncovered widespread translational dysregulation in OCCC, with experimental validation confirming the pro-tumorigenic role of translationally upregulated RBM4. This study bridges a critical gap between genomic, transcriptomic, and proteomic landscapes in OCCC, offering valuable mechanistic insights into its pathogenesis.
    DOI:  https://doi.org/10.1038/s41388-026-03840-7
  6. Biochem Pharmacol. 2026 Jun 01. pii: S0006-2952(26)00453-3. [Epub ahead of print] 118118
    Small peptide encoded by MALAT1 aggravates colitis via upregulating GIP expression in enterocyte.
    Da Teng, Bing Ma, Xinmo Liu, Shaoyou Xia.
      Inflammatory bowel disease is a chronic and relapsing intestinal disorder that is challenging to cure. Enterocytes secrete various small peptides and are closely associated with IBD pathogenesis, but their mechanistic roles remain unclear. Our study identified a novel small peptide encoded by the long non-coding RNA MALAT1 in enteroendocrine K cells, which namedenteroendocrine cells peptide (EECP). The expression of EECP is upregulated in colitis, and its specific knockout suppresses dextran sulfate sodium-induced colitis symptoms, including reduced immune cell infiltration and alleviated intestinal destruction. Mechanistically, EECP enhances the secretion of gastric inhibitory polypeptide in enteroendocrine K cells, which in turn promotes production of pro-inflammatory cytokines in macrophages, thereby exacerbating colitis progression. Further investigation revealed that EECP binds to the transcriptional repressor FOXP1 to regulate gastric inhibitory polypeptide expression. This study uncovers a novel mechanism by which enterocyte modulate colitis development and provides potential therapeutic targets for IBD treatment.
    Keywords:  EECP; Enterocyte; Inflammatory bowel disease; MALAT1
    DOI:  https://doi.org/10.1016/j.bcp.2026.118118
  7. J Transl Med. 2026 Jun 04.
    MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases.
    Carlos A Amado, Juan Agüero, Mayte García-Unzueta, Ana Berja, Bernardo A Lavín, Paula Martín-Audera.
       BACKGROUND: MOTS-c is a mitochondrial-derived microprotein (mitokine) encoded within the 12 S rRNA gene that exerts intracrine, paracrine, and endocrine effects across multiple tissues. Although initially described as a regulator of metabolic homeostasis, growing evidence indicates that MOTS-c also modulates oxidative and toxic stress, inflammation, autophagy, cell death (apoptosis, ferroptosis, pyroptosis, among others), mitochondrial dysfunction, and immune responses-key mechanisms involved in acute and chronic respiratory diseases.
    MAIN BODY: Available experimental and clinical studies suggest that circulating MOTS-c levels are reduced in different forms of acute respiratory distress, while exogenous administration attenuates lung injury in preclinical models. Remote ischemic preconditioning appears to exert part of its protective effects through MOTS-c release. In contrast, chronic respiratory diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea, and asthma are characterized by decreased MOTS-c concentrations, reflecting severe mitochondrial dysfunction and reduced cytoprotective capacity. Preliminary observations suggest increased MOTS-c levels in lung cancer, potentially related to NRF2-mediated antioxidant responses, although these findings require further validation.
    CONCLUSIONS: Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine. Well-designed translational and multicenter clinical studies are needed to determine whether modulation or supplementation of MOTS-c can influence disease progression and clinical outcomes in inflammatory lung diseases.
    Keywords:  COPD; Exacerbation; Inflammation; Lung; MOTS-c; Mitochondria
    DOI:  https://doi.org/10.1186/s12967-026-08398-2
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