bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2026–03–15
two papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Integrative multiomics analysis and CRISPR screening identify functional noncanonical translation loci in the mouse immune system.
  2. Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) primes adrenal cortex metabolism without directly driving steroidogenesis.
  1. bioRxiv. 2026 Feb 24. pii: 2026.02.23.707583. [Epub ahead of print]
    Integrative multiomics analysis and CRISPR screening identify functional noncanonical translation loci in the mouse immune system.
    Eric Malekos, Valeriy Smaliy, Susan Carpenter.
      Ribosome profiling has revealed thousands of noncanonical translation events across mammalian genomes, yet functional characterization has overwhelmingly focused on proliferative fitness in cancer cell lines. Here, we present a comprehensive survey of noncanonical translation in the mouse immune system and its functional consequences in macrophages. By performing a unified Ribo-seq meta-analysis across 20 public mouse leukocyte datasets - spanning macrophages, dendritic cells, neutrophils, B cells, and T cells - we define a compendium of 22,276 noncanonical coding sequences (CDSs), including upstream ORFs (uORFs), downstream ORFs, and ORFs on noncoding RNAs and pseudogenes (ncORFs). Proteogenomic integration with reanalyzed mass spectrometry data prioritizes a high-confidence subset with detectable protein products, including pseudogene-encoded and lncRNA-encoded zinc finger proteins. To move beyond cataloging, we carried out two orthogonal CRISPR screens in immortalized bone marrow-derived macrophages: a fitness screen identifying noncanonical CDSs required for macrophage viability, and a TLR1/TLR2-NFκB reporter screen uncovering CDSs that modulate innate immune signaling. These screens nominate uORFs, several conserved between mouse and human, that exert phenotypic effects on par with their cognate coding sequences. We unexpectedly discovered a family of endogenous retroviral envelope-derived proteins translated in adult myeloid cells. Among these, SYNIR is a full-length syncytin-like membrane glycoprotein that positively regulates NFκB-responsive transcription, while SEMR is a secreted protein with structural homology to the feline leukemia virus accessory protein FeLIX that drives broad transcriptional remodeling of macrophage gene programs upon knockout. Updated single-cell RNA-seq annotations and an interactive UCSC Genome Browser session integrating Ribo-seq, proteomics, and CRISPR screen data are provided as community resources. Together, these findings expand the functional landscape of noncanonical translation in immunity and establish endogenous retroviral proteins as previously unrecognized regulators of macrophage biology.
    DOI:  https://doi.org/10.64898/2026.02.23.707583
  2. Folia Histochem Cytobiol. 2026 Mar 11.
    Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) primes adrenal cortex metabolism without directly driving steroidogenesis.
    Małgorzata Blatkiewicz, Kacper Kaminski, Marta Sobalska-Kwapis, Marta Szyszka, Anna Olechnowicz, Karol Jopek, Marcin Rucinski.
       INTRODUCTION: Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c), a 16-amino acid mitochondrial-derived peptide, regulates cellular metabolism through AMPK and mTOR signaling and exerts protective effects across multiple endocrine tissues. However, its role in adrenal physiology remains unexplored. We hypothesized that MOTS-c establishes "steroidogenic readiness" by priming metabolic pathways rather than directly activating hormone synthesis.
    MATERIAL AND METHODS: Adult male Wistar rats (n = 16) received continuous MOTS-c (0.1 µmol/24 h) or saline via subcutaneous micro-osmotic pumps for 24 hours. Adrenal tissues were analyzed using qRT-PCR, immunohistochemistry, ELISA, and RNA-sequencing.
    RESULTS: MOTS-c showed significantly higher expression in ZF/ZR vs. ZG. MOTS-c treatment did not alter classical steroidogenic genes or circulating corticosterone and aldosterone levels. RNA-seq identified 39 differentially expressed genes, notably upregulation of purinergic receptor P2ry4 (4.3-fold, P < 0.05) - a novel MOTS-C target enhancing calcium signaling. Additional changes included upregulation of Apoc4 and downregulation of stress markers Bag3 and Smurf2, mitochondrial carrier Slc25a30, and peroxisomal factor Pex11a. Gene Set Enrichment Analysis revealed inhibition of cAMP response, mitophagy, and histone deacetylation pathways, alongside activation of cell proliferation, indicating metabolic reprogramming without steroidogenic activation.
    CONCLUSIONS: MOTS-c functions as a metabolic conductor that primes adrenocortical cells for enhanced steroidogenic responsiveness without stimulating basal hormone synthesis. By upregulating calcium signaling, modulating lipid metabolism, downregulating stress-response proteins, and inhibiting mitophagy, MOTS-c establishes a preparatory metabolic state optimized for subsequent ACTH or stress stimulation. These findings reveal a novel preparatory mechanism in adrenal physiology and identify MOTS-c as a potential therapeutic target for HPA axis disorders requiring enhanced adrenal reserve capacity without basal hypercortisolemia.
    Keywords:  AMPK; MOTS-c; adrenal cortex; metabolic priming; mitochondrial-derived peptides; steroidogenesis
    DOI:  https://doi.org/10.5603/fhc.110668
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