bims-micpro 2026-04-05 papers

bims-micpro

Biomed News

on Discovery and characterization of microproteins

Issue of 2026–04–05
six papers selected by
Thomas Farid Martínez, University of California, Irvine

An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2.
MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.
The role and mechanism by which micropeptide WHPP promote refractory wound healing.
Translational control of Toxoplasma gondii differentiation.
Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
Bright side of the dark genome: antigens for next-gen cancer vaccines.

bioRxiv. 2026 Mar 26. pii: 2026.03.24.713967. [Epub ahead of print]

An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2.

Dalton J Huey, Eduardo Guadarrama, Jean-Marc DeKeyser, Carlos G Vanoye, Christine Q Simmons, Qianru Li, Emily K Stroup, Zhe Ji, Alfred L George.

Upstream open reading frames (uORFs) within the 5'-untranslated region (5'-UTR) of mRNA transcripts can regulate protein translation. Despite widespread prevalence within the human genome, they remain unidentified for many clinically relevant genes. A gene frequently associated with neonatal-onset epilepsy is KCNQ2 , which encodes a neuronal voltage-gated potassium channel subunit that functions to dampen neuronal excitability. Heterozygous loss-of-function pathogenic KCNQ2 variants are known to cause a range of neurodevelopmental disorders and epileptic encephalopathies, but there remains an unmet clinical need for patients harboring these variants. We identified a single uORF in KCNQ2 that is highly repressive of protein translation and demonstrated that mutations disabling the uORF start codon enhance translation of encoded potassium channels. Additionally, we show that adenine base editing of the uORF start codon can weaken ribosome engagement at the uORF and enhance translation of the protein in a neuron-like cell line. This study establishes a previously underexplored regulatory feature for KCNQ2 and highlights the importance of understanding uORFs for clinically relevant genes, both for assessing disease risk and therapeutic potential.

DOI: https://doi.org/10.64898/2026.03.24.713967
Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250078. [Epub ahead of print]381(1947):

MTALTCO1: a 259 amino-acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.

Francis Robitaille, Amy Campbell, Aziz Ben Hadj, Sarah Cornet, Ludovic Nadeau-Lachance, Thierry Niaison, Thierry Choquette, Liam Nyffeler, Xavier Roucou, Annie Angers, Sophie Breton.

  Mitochondrial alternative open reading frames (ORFs) substantially broaden the functional scope traditionally attributed to mitochondrial DNA, encoding peptides and proteins that participate in diverse cellular processes. These newly identified ORFs are embedded within annotated sequences, both coding and non-coding, and reveal layers of overlapping genetic information. We report the discovery of MTALTCO1, a 259 amino-acid protein, the longest mitochondrial alternative protein identified to date, encoded by an ORF located within the human cytochrome oxidase 1 gene, in the +3 reading frame. We confirm the expression and mitochondrial origin of MTALTCO1 through multiple independent lines of evidence, including a custom-designed antibody, mass spectrometry-derived peptides, sequence analysis and inhibitors of mitochondrial expression. Despite encoding AGR codons as arginine, contrary to the prevailing view that these function invariably as stop codons in the vertebrate mitochondrial genetic code, MTALTCO1 shows strong evidence of mitochondrial translation, challenging established models of mitochondrial codon usage and gene expression. Co-immunoprecipitations and pulldown assays delineate MTALTCO1's interaction landscape across major cellular pathways. Finally, we present the first in-depth analysis of conservation for a mitochondrial alternative ORF overlapping a reference protein-coding gene and discuss the results in light of MTALTCO1's suggested role in protein scaffolding. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.

Keywords:  alternative proteins; conservation; intrinsically disordered proteins; mitochondria; mitochondrial-derived peptides; mitrochondrial translation; overlapping open reading frame; overprinting; protein function; scaffold proteins

DOI:  https://doi.org/10.1098/rstb.2025.0078
J Transl Med. 2026 Mar 30.

The role and mechanism by which micropeptide WHPP promote refractory wound healing.

Xianglei Wu, Qirui Wang, Ming Hu, Luyu Li, Renpeng Zhou, Ke Liu, Zhen Zhang, Xue Wang.

   BACKGROUND: Full-thickness skin wounds present significant clinical challenges, highlighting an urgent need for accelerated healing strategies. Recent studies have elucidated the involvement of long non-coding RNAs (lncRNAs) in skin wound healing processes, whereby certain lncRNAs regulate key biological functions. Among emerging regulatory factors, small open reading frames (smORFs) within lncRNAs, which encode polypeptides termed small peptides (SEPs), have been implicated in the pathogenesis of various diseases, including tumors and metabolic disorders. Notably, the role of SEPs in wound healing remains unexplored, necessitating further investigation. This study aims to elucidate the function of an SEP, denoted as WHPP (Wound Healing Promoting Peptide), which is encoded by the lncRNA MSTRG22314.1, in the context of skin wound healing.
METHODS: We employed in vitro assays using primary keratinocytes to evaluate the effects of WHPP on cell behavior relevant to wound healing, specifically assessing cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). In vivo analyses involved the administration of WHPP in a rat model of skin injury to assess its therapeutic efficacy on wound closure.
RESULTS: Our findings indicate that WHPP significantly enhances the proliferation and migration of basal keratinocytes while facilitating EMT through the activation of Twist1 protein. Moreover, in vivo experiments revealed that WHPP administration markedly accelerated skin wound healing in rats, corroborated by evidence that WHPP inhibits the degradation of Twist1 protein in keratinocytes.
CONCLUSION: This study represents the first report on the involvement of SEPs, specifically WHPP, in the regulatory mechanisms of wound healing. We suggest that WHPP treatment may provide an innovative therapeutic avenue for patients with chronic and difficult-to-heal wounds. Future research is warranted to delineate the comprehensive molecular pathways influenced by WHPP and to explore its potential applications in clinical settings.

Keywords:  Keratinocytes; SEP; SmORF; Twist1; WHPP; Wounds

DOI:  https://doi.org/10.1186/s12967-026-07732-y
Biosci Rep. 2026 Apr 22. pii: BSR20253672. [Epub ahead of print]46(4):

Translational control of Toxoplasma gondii differentiation.

Fengrong Wang.

  Toxoplasma gondii is a globally prevalent protozoan parasite capable of establishing lifelong infections in its host. While acute infection is often asymptomatic, reactivation of latent bradyzoites can cause severe disease, particularly in immunocompromised individuals. Current therapies are ineffective against chronic infection, underscoring critical gaps in our understanding of bradyzoite biology and the molecular mechanisms governing stage conversion. Recent studies have identified translational control as a central regulator of T. gondii differentiation. This review highlights the roles of canonical translation initiation factors (eIF2α, eIF1.2, and eIF4E1), RNA-binding proteins (RBPs; BFD2/ROCY1, Alba1, and Alba2), and RNA modifications (with pseudouridylation representing the best-characterized modification currently linked to differentiation), as well as alternative splicing and non-coding RNAs in shaping stage-specific translational programs. This review further discusses underexplored mechanisms, including non-canonical initiation pathways, upstream open reading frames, transcript-level RNA modifications, ribosome heterogeneity and rRNA modifications, elongation and termination control, uncharacterized RBPs, and post-translational modifications of translation factors, that may coordinate proteome remodeling during differentiation. Together, established translational regulators and these emerging pathways highlight translational control as a central driver of parasite persistence and a promising therapeutic target for chronic toxoplasmosis.

Keywords:  Alternative splicing; Cell differentiation; Non-coding RNA; RNA editing; RNA-binding proteins; Toxoplasma gondii; Translation; Translation factors

DOI:  https://doi.org/10.1042/BSR20253672
Sci Immunol. 2026 Apr 03. 11(118): eaeb6484

Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.

Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J Van den Eynde, Xin Lu, Mads Gyrd-Hansen.

Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5' untranslated region of TNFRSF1A and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.

DOI: https://doi.org/10.1126/sciimmunol.aeb6484
J Immunother Cancer. 2026 Apr 02. pii: e014075. [Epub ahead of print]14(4):

Bright side of the dark genome: antigens for next-gen cancer vaccines.

Xiao-Song Wang, Bernard A Fox.

  The discovery of cancer's hidden antigen landscape-comprising non-canonical 'dark matter' antigens-has unveiled a vast, untapped reservoir of immune targets for next-generation cancer immunotherapy. While most cancer vaccine strategies of the past decade have focused on mutation-derived neoantigens, studies applying sensitive mass spectrometry methods fail to identify the majority of predicted neoepitopes being presented by tumor human leukocyte antigen (HLA) molecules, potentially explaining negative results of several recent neoantigen vaccine trials. By contrast, peptides from non-canonical open reading frames, aberrant splice products, and non-coding RNAs that derive from short-lived proteins (SLiPs) are readily stabilized in class I HLA, and as a consequence of frequently being undetected in the thymus, have demonstrated strong immunogenicity. Early reports suggest some non-canonical immunopeptides are shared within and sometimes across multiple cancer histologies, with early evidence that some have tumor-promoting functions. Because these SLiPs are degraded so quickly and are stabilized in HLA-I, the intact proteins are postulated to not be accessible to antigen-presenting cells and are not efficiently processed and cross-presented-positioning this 'junk DNA'-derived antigen class as an attractive foundation for off-the-shelf vaccines. Here, we trace four phases of cancer vaccine evolution, review the technological advances that enabled the discovery of the dark immunopeptidome and discuss how these findings challenge established paradigms and reinvigorate interest in shared tumor antigens. By embracing this expanded antigenic universe, the field is poised to overcome key limitations of neoantigen-focused immunotherapy and move toward more universally effective cancer vaccines.

Keywords:  Antigens, Neoplasm; Antigens, Viral, Tumor; DNA, Intergenic; Immunotherapy; Vaccine

DOI:  https://doi.org/10.1136/jitc-2025-014075