bims-micpro 2025-03-30 papers

PeerJ Comput Sci. 2025 ;11 e2733

Protein language model-based prediction for plant miRNA encoded peptides.

Yishan Yue, Henghui Fan, Jianping Zhao, Junfeng Xia.

Plant miRNA encoded peptides (miPEPs), which are short peptides derived from small open reading frames within primary miRNAs, play a crucial role in regulating diverse plant traits. Plant miPEPs identification is challenging due to limitations in the available number of known miPEPs for training. Existing prediction methods rely on manually encoded features, including miPEPPred-FRL, to infer plant miPEPs. Recent advances in deep learning modeling of protein sequences provide an opportunity to improve the representation of key features, leveraging large datasets of protein sequences. In this study, we propose an accurate prediction model, called pLM4PEP, which integrates ESM2 peptide embedding with machine learning methods. Our model not only demonstrates precise identification capabilities for plant miPEPs, but also achieves remarkable results across diverse datasets that include other bioactive peptides. The source codes, datasets of pLM4PEP are available at https://github.com/xialab-ahu/pLM4PEP.

Keywords: Machine learning; Protein language model; miPEPs

DOI: https://doi.org/10.7717/peerj-cs.2733

iScience. 2025 Mar 21. 28(3): 111884

A large-scale sORF screen identifies putative microproteins involved in cancer cell fitness.

Dörte Schlesinger, Christopher Dirks, Carmen Navarro, Lorenzo Lafranchi, Anna Spinner, Glancis Luzeena Raja, Gregory Mun-Sum Tong, Jürgen Eirich, Thomas Farid Martinez, Simon Johannes Elsässer.

The human genome contains thousands of potentially coding short open reading frames (sORFs). While a growing set of microproteins translated from these sORFs have been demonstrated to mediate important cellular functions, the majority remains uncharacterized. In our study, we performed a high-throughput CRISPR-Cas9 knock-out screen targeting 11,776 sORFs to identify microproteins essential for cancer cell line growth. We show that the CENPBD2P gene encodes a translated sORF and promotes cell fitness. We selected five additional candidate sORFs encoding microproteins between 11 and 63 amino acids in length for further functional assessment. Green fluorescent protein fusion constructs of these microproteins localized to distinct subcellular compartments, and the majority showed reproducible biochemical interaction partners. Studying the fitness and transcriptome of sORF knock-outs and complementation with the corresponding microprotein, we identify rescuable phenotypes while also illustrating the limitations and caveats of our pipeline for sORF functional screening and characterization.

Keywords: cancer; cell biology; classification of proteins; methodology in biological sciences; molecular genetics

DOI: https://doi.org/10.1016/j.isci.2025.111884

mBio. 2025 Mar 28. e0012525

Functional characterization of a novel protein-coding circular RNA, circRNA_1193, from the mAAP gene in silkworm and its role in antiviral defense against BmCPV.

Song Li, Zeen Shen, Hongchuan Zhao, Xialing Chen, Qunnan Qiu, Xinyu Tong, Min Zhu, Xing Zhang, Chengliang Gong, Xiaolong Hu.

A novel circular RNA, circRNA_1193, which originates from the membrane alanyl aminopeptidase-like gene in silkworms, was explored for its potential function and regulatory mechanism. We validated the presence of circRNA_1193 in Bombyx mori cytoplasmic polyhedrosis virus (BmCPV)-infected silkworm ovary cell line (BmN) cells through a combination of reverse transcription polymerase chain reaction, Northern blotting, and in situ hybridization. CircRNA_1193 exhibited tissue-specific expression, being highly enriched in the midgut and Malpighian tubules, and displayed a specific response to BmCPV infection, but not to Bombyx mori nucleopolyhedrovirus or lipopolysaccharide. Functional analyses revealed that the overexpression of circRNA_1193 suppressed BmCPV replication, whereas its knockdown increased viral replication. Bioinformatic analyses revealed potential internal ribosome entry sites, m6A methylation sites, and open reading frames (ORFs) within circRNA_1193, suggesting its potential coding capacity. We confirmed the translation of the ORF by constructing a DsRed reporter vector and demonstrating DsRed expression in transfected cells. Furthermore, a mutation of the start codon within circRNA_1193 abolished its antiviral activity, highlighting the crucial role of the translated protein, which is 35 kDa and is designated as VSP35. Furthermore, our data suggest that the formation of circRNA_1193 relies on reverse complementary flanking sequences. These findings unveil a novel protein-coding circular RNA in silkworms that plays a critical role in antiviral defense.
IMPORTANCE: This study identified a novel circular RNA, circRNA_1193, in the silkworm Bombyx mori, and revealed its critical role in antiviral defense against Bombyx mori cytoplasmic polyhedrosis virus (BmCPV). We demonstrated that circRNA_1193 exhibits tissue-specific expression, is upregulated in response to BmCPV infection, and possesses antiviral activity. Importantly, we show that circRNA_1193 encodes the viral protein VSP35, which is essential for its antiviral function. These findings provide new insights into the complex regulatory mechanisms of circular RNAs in antiviral immunity and underscore the potential of circular RNAs as therapeutic targets in viral diseases. The identification of a protein-coding circular RNA with antiviral activity in B. mori has broader implications for understanding the evolution and diversity of host defense mechanisms against viruses.

Keywords: BmCPV; ORF; circRNA_1193; silkworm; virus replication

DOI: https://doi.org/10.1128/mbio.00125-25

Cell Signal. 2025 Mar 25. pii: S0898-6568(25)00180-9. [Epub ahead of print]131 111767

Identification of a new micropeptide altKLF4 derived from KLF4 that influences myeloma chemotherapeutic sensitivity.

Ruosi Yao, Yindi Zeng, Yaxin Zhang, Xu Cao, Jiwei Mao, Wenjing Li, Kailin Xu, Linlin Liu.

Multiple myeloma (MM) is a common yet incurable hematological malignancy characterized by bone marrow infiltration. A major clinical challenge is the resistance to chemotherapy, highlighting the urgent need to better understand the molecular mechanisms underlying chemotherapeutic resistance to available drugs. Recent studies have emphasized the role of micropeptides in solid tumors and leukemia, but their functions in MM remain unclear. In this study, we identified a novel micropeptide, altKLF4, derived from the transcription factor KLF4, which is highly expressed in newly diagnosed myeloma patient samples. We found that ectopic expression of altKLF4 interfered with chemotherapy sensitivity induced by proteasome inhibitors in myeloma cells. Additionally, confocal microscopy and transcriptome sequencing revealed that altKLF4 co-localizes with the mitochondrial inner marker TOMM20 and participates in mitochondria-related biological processes, suggesting that altKLF4 partially localizes to the mitochondria. Mitochondria may also play a role in regulating ferroptosis. Our results further demonstrated that altKLF4 inhibited drug sensitivity and ferroptosis induced by the GPX4 inhibitor RSL3 in multiple myeloma cells through a direct interaction with GPX4. In vivo experiments showed that RSL3 significantly suppressed primary myeloma growth, which could be rescued by the micropeptide altKLF4. Taken together, our study identifies altKLF4 as a novel micropeptide that serves as a potential biomarker for chemotherapeutic resistance in multiple myeloma, offering insights for diagnosis and management of drug-resistant MM.

Keywords: Chemotherapeutic sensitivity; Ferroptosis; KLF4; Micropeptide; Myeloma

DOI: https://doi.org/10.1016/j.cellsig.2025.111767

JACC Basic Transl Sci. 2025 Feb;pii: S2452-302X(24)00324-3. [Epub ahead of print]10(2): 131-147

CircBTBD7-420aa Encoded by hsa_circ_0000563 Regulates the Progression of Atherosclerosis and Construction of circBTBD7-420aa Engineered Exosomes.

Circular RNAs are associated with cardiovascular disease, including coronary artery disease, but the mechanisms have not been completely elucidated. We found a new protein, circBTBD7-420aa, encoded by hsa_circ_0000563. Our results suggest that circBTBD7-420aa may inhibit the abnormal proliferation and migration of human coronary artery smooth muscle cells by promoting SLC3A2 degradation through the ubiquitin-proteasome pathway. In addition, we constructed engineered exosomes loaded with circBTBD7-420aa that can target vascular smooth muscle cells by modifying peptide fragments targeting osteopontin. This study suggests that circBTBD7-420aa may inhibit the progression of atherosclerosis and serve as a new target for the diagnosis and treatment of coronary artery disease.

Keywords: SLC3A2; circular RNA; coronary artery disease; engineered exosomes; translation; ubiquitination

DOI: https://doi.org/10.1016/j.jacbts.2024.09.003