bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2026–06–14
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. PAMP orchestrates proline metabolic rewiring to suppress LUAD via PYCR1 inhibition.
  2. Enhancer RNAs: similarities with both lncRNAs and mRNAs reveal novel functions.
  3. Emerging roles of micropeptides in calcium cycling dysregulation and atrial fibrillation: A review.
  4. The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
  5. Dual Activity Microbial Peptides Catalog.
  6. TRAINSPOTTER: profiling nascent protein N-termini indicative of bacterial translation initiation via deformylation-assisted N-terminomics.
  7. SPAID: a comprehensive database for disease-specific autoantigens in autoimmune disorders.
  1. EMBO Mol Med. 2026 Jun 09.
    PAMP orchestrates proline metabolic rewiring to suppress LUAD via PYCR1 inhibition.
    Yun Ma, Jiani Yi, Chengcai Zheng, Juze Yang, Jia Li, Mengqian Yu, Xinyi Qian, Jiayi Ren, Xiaofan Wu, Yan Lu, Pengyuan Liu.
      Recent advances in next-generation sequencing have revealed that long non-coding RNAs (lncRNAs) can encode functional micropeptides through small open reading frames (sORFs), altering the perception of the non-coding genome. In this study, we identified a 48-amino acid micropeptide named PAMP (proline-associated micropeptide), encoded by the lncRNA PSMA3-AS1, as a novel tumor suppressor in lung adenocarcinoma (LUAD). PAMP is significantly downregulated in LUAD tissues and positively correlates with favorable prognosis. Functional assays demonstrated that PAMP inhibits LUAD cell proliferation in vitro and suppresses tumor growth in vivo. Mechanistically, PAMP directly interacts with PYCR1, a key enzyme in proline biosynthesis. Structural modeling and mutagenesis revealed that the PAMP-F16 and PYCR1-N123 residues are critical for the interaction, resulting in the inhibition of PYCR1 enzymatic activity and decreased proline accumulation. Notably, synthetic PAMP administration recapitulates these anti-tumor effects, effectively reducing intracellular proline levels and impairing tumor progression in cellular and animal models. Together, our findings uncover a previously uncharacterized lncRNA-encoded micropeptide that orchestrates proline metabolic reprogramming to restrain LUAD development, offering new opportunities for metabolic intervention in precision oncology.
    DOI:  https://doi.org/10.1038/s44321-026-00460-2
  2. RNA Biol. 2026 Dec;23(1): 1-21
    Enhancer RNAs: similarities with both lncRNAs and mRNAs reveal novel functions.
    Pavel A Vlasov, James L Manley.
      Cells produce numerous types of RNAs. Among these, transcripts produced by RNA polymerase II include protein-coding mRNAs as well as a variety of long noncoding RNAs. In this latter group, enhancer (e) RNAs constitute a class of RNAs transcribed from enhancer sites. Although eRNAs are typically unstable and degraded rapidly, multiple roles related to enhancer function have been suggested. But eRNAs also share similarities with mRNAs, such as in a limited number the presence of translated open reading frames. Indeed, other "noncoding" RNAs have also been found to contain coding sequences, and together these transcripts blur the line between coding and noncoding. Here, we review current models of eRNA function, the discoveries that led to them, and additional functions, specifically the potential for translation. We also review the characteristics of proteins encoded by such "noncoding" transcripts, and their possible implications regarding the function and evolution of both eRNAs and mRNAs.
    Keywords:  Enhancers; RNA; RNA processing; eRNA; lncRNA; translation
    DOI:  https://doi.org/10.1080/15476286.2026.2682066
  3. Int J Biol Macromol. 2026 Jun 06. pii: S0141-8130(26)02850-3. [Epub ahead of print]370 152923
    Emerging roles of micropeptides in calcium cycling dysregulation and atrial fibrillation: A review.
    Punyadhara Pani, Gourabamani Swalsingh, Sakthivel Sadayappan, Naresh Chandra Bal.
      Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia globally, marked by chaotic electrical impulses and irregular atrial contraction. At the cellular level, defective calcium (Ca+2) handling plays a central role in AF pathogenesis, with the sarco/endoplasmic reticulum Ca+2-ATPase (SERCA) pump being a critical determinant of intracellular Ca+2 reuptake and myocardial relaxation. Recent research has uncovered a class of small transmembrane micropeptides, phospholamban (PLB), sarcolipin (SLN), dwarf open reading frame (DWORF), myoregulin (MLN), endoregulin (ELN) and another-regulin (ALN), that directly modulate SERCA activity. Interestingly, these micropeptides exhibit chamber-specific expression and diverse regulatory mechanisms, functioning as inhibitors, uncouplers or facilitators of SERCA activity and are increasingly linked to atrial arrhythmogenesis. This review synthesizes current understanding on function of SERCA micropeptides, highlighting their distinct roles in atrial versus ventricular excitation-contraction (E-C) coupling. We explore evidence from genetically modified animal models and patient-derived data to elucidate how dysregulation of these peptides, particularly SLN and PLB, contributes to abnormal EC-coupling like Ca+2 cycling, delayed afterdepolarizations, oxidative stress and atrial remodeling. We also examine the influence of systemic metabolic regulators, such as thyroid hormones, catecholamines, dexamethasone and various exercise paradigms on micropeptide expression and function, offering insight into their intersection with AF progression. By dissecting the spatial, temporal and metabolic regulation of SERCA micropeptides, this review aims to offer current understanding about chamber-specific modulation of Ca+2 homeostasis and use these insights towards treatment of AF.
    Keywords:  Atrial fibrillation; Calcium handling; Micropeptides; Phospholamban; SERCA; Sarcolipin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152923
  4. PLoS Genet. 2026 Jun 10. 22(6): e1012203
    The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
    Hidetaka Katow, Thao Nguyen, Sarah Hyunsoh Park, Hyung Don Ryoo.
      The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially translating the transcription factor ATF4, a process regulated by upstream open reading frames (uORFs) in its 5' leader. In Drosophila, Xrp1 is another transcription factor induced during the ISR, but the precise underlying mechanism remains unclear. Here, we report that Xrp1 induction in response to ER stress is regulated by both its uORFs and the main ORF sequence. Xrp1 has seven splice isoforms, and the two predominant transcripts expressed in eye imaginal discs contain uORFs. Expressing the ER stress-imposing ninaEG69D transgene in this tissue induced Xrp1 expression without significantly changing the Xrp1 splice isoform composition. The uORF-containing 5' leaders, particularly the AUG codon of the second uORF, inhibited DsRed expression when placed upstream of the reporter. Unlike ATF4, the uORF-containing 5' leader alone was insufficient to mediate the main ORF induction, but Xrp1 induction occurred in ninaEG69D-expressing discs when Xrp1's 5' leader and the main ORF sequence were both present. Functionally, Xrp1 was required to maintain the integrity of Drosophila photoreceptors exposed to constant light. In a different disease model, parkin mutants activated Xrp1 target gene expression in specific tissues and Xrp1 loss enhanced the viability of parkin mutant flies during adult eclosion. These results provide molecular and pathological insights into Xrp1 regulation and function in disease models.
    DOI:  https://doi.org/10.1371/journal.pgen.1012203
  5. Sci Data. 2026 Jun 08.
    Dual Activity Microbial Peptides Catalog.
    Özlem Sağıroğlu, Muzaffer Arıkan.
      Antibiotic resistance and cancer represent two of the most pressing global health challenges. In recent years, peptides have emerged as a promising molecular class to address these issues, with antimicrobial peptides (AMPs) in particular attracting attention as alternatives to conventional antibiotics. Notably, some AMPs have also been found to exhibit anticancer peptide (ACP) properties, thus possessing dual activity. Despite this potential, ACPs remain underrepresented in current databases compared to AMPs, largely due to the under-exploration of microbial sources. In this study, we adopted a consensus-based strategy using three ACP prediction tools and two AMP prediction tools to identify candidate peptides with dual activity. Using these tools, we screened a total of 124,051,427 microbial peptides from publicly available small open reading frame (smORF) catalogues and identified 40,251 non-toxic peptides that display dual activity. These were compiled into Dual Activity Microbial Peptides Catalog (DAMPC), a curated and searchable resource of dual-activity, non-toxic microbial peptide sequences.
    DOI:  https://doi.org/10.1038/s41597-026-07521-8
  6. Nucleic Acids Res. 2026 Jun 08. pii: gkag587. [Epub ahead of print]54(11):
    TRAINSPOTTER: profiling nascent protein N-termini indicative of bacterial translation initiation via deformylation-assisted N-terminomics.
    Petra Van Damme.
      Accurate delineation of bacterial translation initiation sites (TISs) remains a major challenge, as conventional genome annotation and ribosome profiling (Ribo-seq) often lack the resolution to discriminate closely spaced start codons. To overcome these limitations, we developed TRAINSPOTTER (TRAnslation INitiation SPOTTER), a deformylation-assisted N-terminomics workflow that enables direct, proteome-wide detection of nascent N-termini indicative of active translation initiation. TRAINSPOTTER exploits the universal N-terminal formylation of initiator methionine in bacteria: in vitro enzymatic deformylation by peptide deformylase (PDF) generates a diagnostic hydrophilic shift, allowing selective isolation of previously formylated, initiation-derived peptides by COFRADIC-based chromatography. Optional in vivo PDF inhibition transiently enriches formylated N-termini, primarily enhancing detection sensitivity. Integration of pulse SILAC (Stable Isotope Labeling by Amino acids in Cell Culture) labeling confirmed that deformylation-shifted peptides represent newly synthesized N-termini, validating TRAINSPOTTER's specificity for nascent translation products. Application to Escherichia coli enabled precise mapping of >1000 TIS-indicative N-termini, including numerous alternative and near-cognate start sites, providing direct proteomic evidence for co-expressed N-terminal proteoforms. The method complements and refines Ribo-seq datasets, offering amino acid-level resolution for otherwise ambiguous initiation events. TRAINSPOTTER thus establishes a robust biochemical framework for proteome-wide identification of TISs and advances the experimental annotation of bacterial proteomes.
    DOI:  https://doi.org/10.1093/nar/gkag587
  7. Adv Biotechnol (Singap). 2026 Jun 08. pii: 23. [Epub ahead of print]4(2):
    SPAID: a comprehensive database for disease-specific autoantigens in autoimmune disorders.
    Shunhui Deng, Fangfang Wei, Ya Pang, Luowanyue Zhang, Shengyao Zhi, Tianjian Chen, Zhixiang Zuo, Jian Ren, Yubin Xie, Xiaotong Luo.
      Autoimmune diseases (ADs) are chronic inflammatory disorders characterized by complex etiologies and significant diagnostic challenges. Although autoantigens are critical for precision diagnosis and therapy, much of the immunogenic landscape remains unexplored due to the historical focus on canonical proteins. Here, we developed SPAID ( https://spaid.renlab.cn ), a comprehensive resource for candidate autoantigen discovery across 14 ADs that integrates canonical and non-canonical proteins within a two-level evidence framework. The validated level contains proteins associated with experimentally confirmed epitopes from T-cell assays and major histocompatibility complex (MHC) ligand assays. The proteomics-based level contains proteins identified by mass spectrometry (MS) from human samples, further annotated with differential expression patterns, immunogenicity scores, and functional features to support candidate autoantigen discovery and further validation. By combining validated evidence with proteomics-based evidence, SPAID enables the comprehensive characterization of candidate autoantigen repertoires and facilitates mechanistic investigation into antigen origins and pathogenic recognition. Overall, SPAID provides a foundational resource for advancing antigen-centered research and developing novel diagnostic and therapeutic strategies in autoimmunity.
    Keywords:  Autoimmune diseases; Candidate autoantigens; Non-canonical proteins; Proteomics; Small peptides
    DOI:  https://doi.org/10.1007/s44307-026-00117-8
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