bims-micpro 2025-11-16 papers

Genome Biol. 2025 Nov 10. 26(1): 382

Translational regulation plasticity shapes wheat grain adaptation to heat stress.

Yongming Chen, Yiwen Guo, Mengsi Ma, Yongfa Wang, Weilong Guo, Zhaorong Hu, Mingming Xin, Yingyin Yao, Zhongfu Ni, Qixin Sun, Huiru Peng.

BACKGROUND: Extremely high temperatures due to global warming are increasingly threatening crop production, and plants have evolved highly sophisticated mechanisms to respond to harsh environmental stresses and survive. At the translational level, how bread wheat responds to high temperatures remains largely unknown.
RESULTS: We use ribosome profiling and high-throughput sequencing to investigate the translatome of wheat grains in response to high temperatures. Our study reveals that heat stress profoundly reshapes the translatomic landscapes, significantly affecting the translation of the mRNAs involved in the translation process, grain development, and heat stress response. A subset of the upstream open reading frames (uORFs) and RNA-binding proteins specifically link to their potential target with associated translatomic changes under high temperature. Divergent translation of duplicated genes is affected by the imbalanced expression of uORFs. Interestingly, the high temperature stimulates expression of small ORFs in long non-coding RNAs (lORFs). Microproteins encoded by key heat-responsive lORFs localize to cellular regions including the nucleus, endoplasmic reticulum, and P-body, and interact with heat shock proteins. Furthermore, the microprotein and RNA-binding protein contribute to the heat tolerance variation among wheat accessions.
CONCLUSIONS: This study provides new insights into the translational regulatory mechanism in wheat heat tolerance, accelerating genetic improvements in crops for optimal climate resilience.

Keywords: Bread wheat; Heat stress; Microprotein; Translational regulation; uORF

DOI: https://doi.org/10.1186/s13059-025-03848-4

Nucleic Acids Res. 2025 Oct 28. pii: gkaf1072. [Epub ahead of print]53(20):

Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response.

Lorenzo Lafranchi, Glancis Luzeena Raja, Alberto M Arenas, Anna Spinner, Kovi R Shrung, Maximilian Hornisch, Dörte Schlesinger, Carmen Navarro Luzon, Linus Brinkenstråhle, Rui Shao, Ilaria Piazza, Janne Lehtiö, Rui M M Branca, Simon J Elsӓsser.

Microproteins encoded by short open reading frames (sORFs) of <100 codons have been predicted to constitute a substantial fraction of the eukaryotic proteome. However, the relevance and roles of a majority of microproteins remain undefined, as only a small fraction of these intriguing cellular players have been characterized in-depth so far. Here, we use pooled overexpression screens with a library of 11 338 sORFs to overcome the challenge of elucidating which of the thousands of putative translated sORFs are biologically functional. As a proof-of-concept, we performed a phenotypic screen to identify sORFs protecting cells from treatment with the nucleotide analogue 6-thioguanine. With this approach, we identified two cytoprotective microproteins: altDDIT3 and PIPPI. PIPPI is encoded within the LCR16a core duplicon of the Morpheus/NPIP gene cluster. We show that PIPPI modulates the cellular response to protein folding stress in the endoplasmic reticulum (ER) and interacts with proteins in the same pathway, including protein disulfide isomerase ERp44. PIPPI overexpression protects, while PIPPI knockdown sensitizes cells to ER stress. Besides providing mechanistic insights into a new microprotein, this study highlights the power of using pooled overexpression screens to identify functional microproteins.

DOI: https://doi.org/10.1093/nar/gkaf1072

Adv Exp Med Biol. 2026 ;1484 353-384

Recent Characterization of Key Proteins to Combat Tuberculosis.

Parissa Farnia, Ali Akbar Velayati, Jalaledin Ghanavi, Poopak Farnia.

Recent large-scale proteogenomic analyses of Mycobacterium tuberculosis (Mtb) have significantly deepened our understanding of its proteome by delineating two major classes of proteins: canonical proteins and microproteins. Canonical proteins, encoded by well-annotated open reading frames (ORFs), perform essential functions in fundamental cellular processes, including DNA replication, metabolism, virulence regulation, and adaptation to stress. Concurrently, growing attention has been directed toward microproteins, small polypeptides translated from previously unannotated small ORFs, which have increasingly been recognized as key modulators of bacterial growth, persistence, and antibiotic response. Microproteins commonly exhibit structural characteristics such as intrinsically disordered regions, signal peptides, and transmembrane domains, enabling their participation in diverse cellular pathways, including membrane dynamics, signal transduction, and transcriptional regulation. These insights highlight the remarkable regulatory complexity and proteomic versatility that underpin Mtb's ability to adapt to host-imposed stress conditions. A significant advancement is the emerging understanding of conserved hypothetical proteins (CHPs), a long-overlooked group previously considered functionally ambiguous. Recent structural and functional characterizations have uncovered critical roles for many CHPs in vital biological processes, such as cell wall biosynthesis, DNA maintenance, metabolic control, and environmental stress responses. Notably, several newly characterized members of both microproteins and CHPs have surfaced as promising vaccine candidates owing to their strong immunogenicity and as attractive drug targets due to their essentiality and amenability to structural studies. Additionally, some exhibit potential as diagnostic biomarkers based on their infection-specific expression and recognition by the host immune system. Collectively, this expanded repertoire, especially the newly characterized proteins, significantly enhances our understanding of Mtb pathogenesis, adaptability, and persistence.

Keywords: Microproteins; Mycobacterium tuberculosis; PE/PPE family; Proteogenomics; Stress response microproteins; Subunit vaccines; Type II toxin-antitoxin (TA) proteins

DOI: https://doi.org/10.1007/978-3-031-96883-9_10

Mol Cell. 2025 Nov 12. pii: S1097-2765(25)00863-9. [Epub ahead of print]

Monitoring the complexity and dynamics of mitochondrial translation.

Taisei Wakigawa, Mari Mito, Yushin Ando, Haruna Yamashiro, Kotaro Tomuro, Haruna Tani, Kazuhito Tomizawa, Takeshi Chujo, Asuteka Nagao, Takeo Suzuki, Osamu Nureki, Fan-Yan Wei, Yuichi Shichino, Yuzuru Itoh, Tsutomu Suzuki, Shintaro Iwasaki.

Since mitochondrial translation leads to the synthesis of the essential oxidative phosphorylation (OXPHOS) subunits, exhaustive and quantitative delineation of mitoribosome traversal is needed. Here, we developed a variety of high-resolution mitochondrial ribosome profiling derivatives and revealed the intricate regulation of mammalian mitochondrial translation. Harnessing a translation inhibitor, retapamulin, our approach assessed the stoichiometry and kinetics of mitochondrial translation flux, such as the number of mitoribosomes on a transcript, the elongation rate, and the initiation rate. We also surveyed the impacts of modifications at the anticodon stem loop in mitochondrial tRNAs (mt-tRNAs), including all possible modifications at the 34th position, in cells deleting the corresponding enzymes and derived from patients, as well as in mouse tissues. Moreover, a retapamulin-assisted derivative and mito-disome profiling revealed mitochondrial translation initiation factor (mtIF) 3-mediated translation initiation from internal open reading frames (ORFs) and programmed mitoribosome collision sites across the mitochondrial transcriptome. Our work provides a useful platform for investigating protein synthesis within the energy powerhouse of the cell.

Keywords: MELAS; Ribo-Seq; disome; kinetics; mitochondria; mitoribosomes; mtIF3; ribosome profiling; tRNA modification; translation

DOI: https://doi.org/10.1016/j.molcel.2025.10.022

J Transl Med. 2025 Nov 11. 23(1): 1266

-A novel peptide SMIM45-107aa promotes HCC progression via MTDH pathways and its anticancer peptide derivative.

Yan An, Xiangyang Shi, Wentao Huang, Mingyi Shang, Guang-Zhi Jin.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies, and the treatment options are limited. Growing evidence shows that long non-coding RNAs (LncRNAs) encode peptides, suggesting that lncRNAs-derived peptides may play a role in HCC progression and explore their potential as therapeutic targets.
METHODS: We used RNA-sequencing and bioinformatics analysis to identify a 107-amino acid peptide, SMIM45-107aa, encoded by LINC00634. The expression levels and prognostic significance of SMIM45-107aa in HCC tissues were assessed by immunohistochemistry (IHC) and Kaplan-Meier. Wound-healing and cell colony formation evaluate the effects of SMIM45-107aa on cell migration and proliferation. A mouse xenograft model was used to examine the tumor formation. Interactions between SMIM45-107aa and MTDH were explored and the effects on MTDH ubiquitination were investigated by immunoprecipitation. Proteomic analysis and Western blotting confirmed the mechanism of SMIM45-107aa effected HCC. Additionally, a short peptide, peptide 5 derived from SMIM45-107aa was analyzed by cell migration in SK-Hep1 cells and by zebrafish model.
RESULTS: SMIM45-107aa was highly expressed in HCC tissues and associated with poor prognosis. It promoted cell migration and proliferation in vitro and tumor formation in vivo. SMIM45-107aa interacted with MTDH, inhibiting its ubiquitination and stabilizing the protein. Proteomic and Western blot analysis revealed that SMIM45-107aa upregulated MGST1 and phosphorylated AKT (pAKT). Importantly, peptide 5 inhibited SMIM45-107aa-induced cell migration and demonstrated anticancer activity in zebrafish models.
CONCLUSION: We identified SMIM45-107aa, a novel peptide encoded by LINC00634, which promoted HCC progression via the MGST1-pAKT-MTDH axis. The derived peptide 5 exhibited anticancer activity, suggesting a potential therapeutic strategy for HCC.

Keywords: Hepatocellular carcinoma; Interaction protein MTDH; MGST1; SMIM45-107aa; SMIM45-107aa-derived peptide

DOI: https://doi.org/10.1186/s12967-025-07179-7

J Exp Bot. 2025 Nov 12. 76(19): 5629-5633

Peptides: powerful, pervasive, and full of potential.

Alyssa Kearly.

Small peptides are a diverse and biologically integral group of biomolecules that, due to their organic nature and multitude of functions, are poised to be attractive targets for commercialization and bioengineering in a world that must grapple with changes in climate and societal needs. In this Special Issue, discussions of peptides both novel and well-characterized highlight the multifaceted diversity of these functional biomolecules, emphasize that there is still so much to discover, and stress their potential not only for practical applications, but also for shaping our understanding of fundamental biological principles.

Keywords: Abiotic stress; bioengineering; biotic stress; development; dipeptides; sORF-encoded peptides; signaling peptides

DOI: https://doi.org/10.1093/jxb/eraf379