bims-micpro 2025-12-21 papers

Microlife. 2025 ;6 uqaf038

Guided tour through the small protein landscape of Methanosarcina mazei using proteomics and biochemical approaches.

Eva Herdering, Liam Cassidy, Philipp T Kaulich, Jürgen Bartel, Sandra Maaß, Katrin Weidenbach, Andreas Tholey, Ruth A Schmitz.

Small open reading frame (small ORF) encoded proteins fulfil important roles in many cellular processes. In the methanoarchaeon Methanosarcina mazei, numerous small proteins have previously been identified under different nitrogen-availabilities, with only few being subject to functional characterization. Consequently, a detailed expression analysis of small proteins translated under other stress conditions, in conjunction with conservation and sequence-based analyses, may reveal interesting candidates for future downstream analyses. Here, we investigated the small proteome of M. mazei under five growth conditions. By enriching the low molecular weight proteome and combining top-down and bottom-up proteomic analysis, a total of 234 small proteins were validated on protein level, of which 130 were found in top-down proteomics analysis, which were associated with 408 proteoforms. Aiming to unravel functions of the large number of small proteins, we performed sequence-based clustering with emphasis on the presence of characteristic motifs. Thereby, ferredoxin-like small proteins with putative iron-sulphur (Fe-S) cluster binding-sites, as well as possible zinc-binding proteins, both with distinct cysteine motifs, were identified. We further analysed heterologously expressed representatives of the ferredoxin-like and putative zinc-binding small proteins, confirming the zinc-binding capability of two small proteins of the latter group via inductively coupled plasma-mass spectrometry. Overall, the detailed analysis of the M. mazei small proteome under different growth conditions, using various proteomics approaches, as well as sequence-based analyses and biochemical approaches targeting specific protein candidates, represents a key step in systematically uncovering the functions of small proteins in M. mazei.

Keywords: LC-FAIMS-MS/MS; Methanosarcina mazei; bottom-up proteomics; proteoforms; small proteins; top-down proteomics

DOI: https://doi.org/10.1093/femsml/uqaf038

Cell Rep. 2025 Dec 12. pii: S2211-1247(25)01476-7. [Epub ahead of print]44(12): 116704

Multi-omics-guided characterization of neoantigens improves patient stratification and potentiates combinatorial immunotherapy in glioma.

Yingying Ma, Yangyang Cai, Jiaxin Yang, Zheng Zhao, Zefeng Chen, Dezhong Lv, Jiaxin Yu, Changbo Yang, Kefan Liu, Mengqian Zeng, Han Guo, Kang Xu, Qinghua Jiang, Hang Yin, Juan Xu, Yongsheng Li.

The identification of tumor-derived neoantigens that elicit an immune response has led to significant advancements in cancer immunotherapy. We comprehensively investigated the neoantigen atlas in Chinese glioma patients via the integration of whole-exome sequencing, transcriptome, and ribosome profiling. We further proposed MINER (Multi-omics Integration for NEoantigen Recognition) to prioritize neoantigens that integrate HLA-I binding and the TCR response to increase accuracy. In particular, we emphasized the importance of non-canonical open reading frames in neoantigen generation and demonstrated that both gene fusions and somatic mutations contribute to the production of neoantigens complementally. We identified a novel subtype (neo_W) of IDH-wildtype glioma, which was characterized by a higher neoantigen burden and correlated with better survival outcomes. Finally, we experimentally validated therapeutic combinations of immune checkpoint inhibitors that target the RAS-RAF-MEK-ERK signaling pathway for treatment of neo_W glioma patients. Multi-omics-guided characterization of neoantigens provides valuable knowledge for precision therapy of glioma.

Keywords: CP: cancer; CP: immunology; cancer immunotherapy; computational method; glioma; neoantigen; therapeutic combinations

DOI: https://doi.org/10.1016/j.celrep.2025.116704

RNA. 2025 Dec 15. pii: rna.080654.125. [Epub ahead of print]

How Tailored Ribo-Seq Methods Probe Unique Translation Events.

James Marks, Sezen Meydan.

Ribosome profiling (Ribo-seq) is a next-generation, high-resolution sequencing technique that captures ribosome-protected mRNA fragments to map ribosome positions across the transcriptome. This method serves as a powerful proxy for global translational activity by revealing where ribosomes engage with mRNAs. Recent advances have expanded the utility of Ribo-seq to resolve distinct ribosome populations, including initiating ribosomes, small subunits, collided ribosomes, mitochondrial ribosomes, and those associated with specific translation factors or localized to subcellular compartments. These methodological advances have significantly broadened the scope of Ribo-seq, enabling new insights into the molecular mechanisms that govern translation across diverse eukaryotic systems. In this mini-review, we highlight key innovations in Ribo-seq technology and discuss how they have deepened our understanding of the spatial, temporal, and regulatory dimensions of translational control.

Keywords: Ribo-seq; next-generation sequencing; ribosome; ribosome profiling; translation regulation

DOI: https://doi.org/10.1261/rna.080654.125

Carcinogenesis. 2025 Dec 18. pii: bgaf092. [Epub ahead of print]

LncRNA-encoded peptide LRRC75A-AS1-ORF3 suppresses anti-tumor immunity in colorectal cancer through mitophagy-mediated attenuation of cGAS-STING signaling.

Qi Wu, Zhun Li, Xinxin He, Shuhui Yu, Mengrou Zhang, Hui Mo, Saiqi He, Jianming Li, Wen Ni.

Long non-coding RNAs (lncRNAs) serve as pivotal regulators of diverse physiological activities through their interactions with different biomolecules, and their aberrant expression frequently contributes to tumorigenesis and malignant progression. Emerging evidence has demonstrated that certain lncRNAs contain open reading frames (ORFs) that can generate useful short peptides, which influence cancer-related physiological and pathological pathways via diverse mechanisms. In this research, we identified that the lncRNA LRRC75A-AS1 encodes a conserved peptide consisting of 102 amino acids, designated as LRRC75A-AS1-ORF3. Notably, this peptide acts independently of the non-coding RNA itself to suppress anti-tumor immune responses and promote colorectal cancer (CRC) progression. Mechanistically, LRRC75A-AS1-ORF3 is localized in the mitochondria, where it induces mitophagy, thereby eliminating cytosolic mitochondrial DNA (mtDNA) and downregulating the cGAS-STING signaling pathway. Our findings reveal a previously uncharacterized mechanism by which LRRC75A-AS1-ORF3 impairs anti-tumor immunity, thereby presenting a novel immunotherapeutic target for CRC treatment.

Keywords: Colorectal Cancer; LncRNA-encoded peptide LRRC75A-AS1-ORF3; anti-tumor immunity; cGAS-STING signaling; mitophagy

DOI: https://doi.org/10.1093/carcin/bgaf092

Cardiovasc Diabetol. 2025 Dec 13.

The SERCA-PLN-DWORF axis in cardiometabolic disease: mechanisms and therapeutic perspectives.

Ok-Hee Kim, Seung Wan Noh, Jun-Su Choi, YunJae Jung, Byung-Chul Oh.

Intracellular calcium (Ca2+) homeostasis is a central determinant of cardiometabolic physiology, integrating excitation-contraction coupling, metabolic signaling, and stress adaptation across multiple organs. The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), regulated by the micropeptides phospholamban (PLN) and dwarf open reading frame (DWORF), governs ER/SR Ca2+ reuptake and thereby shapes Ca2+-dependent signaling dynamics. Dysregulation of the SERCA-PLN-DWORF axis is increasingly recognized as a shared pathogenic mechanism in type 2 diabetes-related complications, including diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF), where reduced SERCA2a activity prolongs diastolic Ca2+ clearance and promotes calcineurin-NFAT activation and mitochondrial Ca2⁺ overload. In the liver, loss of SERCA2b activity promotes chronic ER stress, Ca2+-phosphoinositide complex formation, insulin resistance, and fibrotic activation, thereby linking Ca2+ dysregulation to progressive metabolic liver injury in metabolic dysfunction-associated fatty liver disease (MAFLD) and steatohepatitis (MASH). These observations position Ca2+ dysregulation as a unifying mechanism across the cardiometabolic disease continuum, spanning myocardial dysfunction, systemic insulin resistance, and progressive fatty liver disease. Therapeutic strategies targeting the SERCA-PLN-DWORF axis, including SERCA activators, PLN-directed antisense oligonucleotides, DWORF gene therapy, and CRISPR-based modulation, have demonstrated efficacy in preclinical models by improving Ca2⁺ handling and alleviating metabolic or contractile stress. Further studies are required to determine the translational feasibility, long-term safety, and optimal patient subsets for SERCA-targeted interventions in cardiometabolic disease.

DOI: https://doi.org/10.1186/s12933-025-03023-w

Eur J Immunol. 2025 Dec;55(12): e70102

Decoding the Cryptic Proteome Between Antigens and Novel Functional Proteins.

Emma G Bawden, Sebastian Amigorena, Yago A Arribas.

The widespread translation of cryptic proteins derived from the non-coding genome expands the complexity of the human proteome. A vast majority of cryptic proteins are expressed at low levels, rapidly degraded and efficiently presented on class I major histocompatibility complexes (MHC-I). On the other hand, some cryptic proteins are stable and functional and may integrate into the proteome through ongoing selective pressures. Herein, we propose a model in which the translation of cryptic proteins increases the diversity of functional proteins on which evolution can act and, during this trial-and-error process, provides a valuable source of antigens for immunosurveillance.

Keywords: DRiPs; antigen presentation; cryptic proteome; immunopeptidomics; ribosome profiling

DOI: https://doi.org/10.1002/eji.70102