bims-micpro 2025-08-31 papers

Bioessays. 2025 Aug 22. e70058

Mitochondrial Microproteins: Emerging Regulators in Neurodevelopment and Neurodegeneration.

Nada Borghol, Sozerko Yandiev, Julien Courchet.

Recent advances in genomics uncovered a large number of microproteins, which are peptides of less than 100 amino-acids encoded by small open reading frames. In contrast to their identification, the validation of the functions of microproteins remains challenging. Especially, what are their biological functions in the cell and how this relates to disease conditions are still largely unknown. Although microproteins ensure a plethora of cellular functions, recent evidence demonstrate that they may disproportionately affect cellular metabolism. In this review, we will address the roles of mitochondrial-targeted microproteins, and especially how this class of protein regulates neuronal metabolism in neurodevelopment and neurodegeneration, and may contribute to axonal and dendritic metabolic disorders.

Keywords: metabolism; microproteins; mitochondria; neurodegeneration; neurodevelopment; neuron

DOI: https://doi.org/10.1002/bies.70058

Nat Commun. 2025 Aug 27. 16(1): 8008

Upstream open reading frame translation enhances immunogenic peptide presentation in mitotically arrested cancer cells.

Alexander Kowar, Jonas P Becker, Rossella Del Pizzo, Zhiwei Tang, Julien Champagne, Kathrin Wellach, Kiana Samimi, Ariel Galindo-Albarrán, Pierre-René Körner, Jasmine Montenegro Navarro, Andrés Elía, Fiona Megan Tilghman, Hanan Sakeer, Marco Antonio Mendoza-Parra, Angelika B Riemer, Reuven Agami, Fabricio Loayza-Puch.

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5' untranslated region (5' UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.

DOI: https://doi.org/10.1038/s41467-025-63405-2

Biomolecules. 2025 Jul 25. pii: 1080. [Epub ahead of print]15(8):

Comparative Analysis of Testicular Transcriptional and Translational Landscapes in Yak and Cattle-Yak: Implications for Hybrid Male Sterility.

Mengli Cao, Shaoke Guo, Ziqiang Ding, Liyan Hu, Lin Xiong, Qianyun Ge, Jie Pei, Xian Guo.

Cattle-yak, a hybrid of yak and cattle, exhibits significant heterosis but male infertility, hindering heterosis fixation. Although extensive research has been conducted on transcriptional mechanisms in the testes of cattle-yak, the understanding of their translational landscape remains limited. In this study, we characterized the translational landscape of yak and cattle-yak based on Ribo-seq technology integrated with RNA-seq data. The results revealed that gene expression was not fully concordant between transcriptional and translational levels, whereas cattle-yak testes exhibited a stronger correlation across these two regulatory layers. Notably, genes that were differentially expressed at the translational level only (MEIOB, MEI1, and SMC1B) were mainly involved in meiosis. A total of 4,236 genes with different translation efficiencies (TEs) were identified, and the TEs of most of the genes gradually decreased as the mRNA expression level increased. Further research revealed that genes with higher TE had a shorter coding sequence (CDS) length, lower GC content, and higher normalized minimum free energy in the testes of yaks, but this characteristic was not found in cattle-yaks. We also identified upstream open reading frames (uORFs) in yak and cattle-yak testes, and the sequence characteristics of translated uORFs and untranslated uORFs were markedly different. In addition, we identified several short polypeptides that may play potential roles in spermatogenesis. In summary, our study uncovers distinct translational dysregulations in cattle-yak testes, particularly affecting meiosis, which provides novel insights into the mechanisms of spermatogenesis and male infertility in hybrids.

Keywords: Ribosomal footprints; cattle–yak; open reading frames; testis; translation efficiency

DOI: https://doi.org/10.3390/biom15081080

Adv Sci (Weinh). 2025 Aug 27. e07713

Single-Cell Dissection of the Biological Function and Molecular Features Underlying the Micropeptide LSMEM1 in Kidney.

Peimin Liu, Hong Zhang, Shanzhi Yang, Jiaoqing Li, Danfeng Wu, Haosen Xu, Huan Jiang, Yi Jing, Guoxiang Jin, Ruobing Liu, Ning Fan, Xiaoyan Bai.

Advances in computational biology and large-scale transcriptome analysis have revealed an increasing number of short open reading frames (sORFs) encoding functional peptides. These small proteins or micropeptides can function independently or exert their biological functions by binding to and/or regulating larger regulatory proteins. LSMEM1 (leucine rich single-pass membrane protein 1, also known as C7orf53) has been found to be significantly upregulated in chronic kidney disease (CKD). In the present study, the molecular structure is aimed to elucidate and function of LSMEM1 and dissect its implications both in physiological and pathophysiological condition. Single-cell transcriptome sequencing (scRNA-seq) technology is used to examine the transcriptional state and biological processes of Lsmem1-/- mice kidneys. Experiments are conducted to verify these biological processes in both physiological and disease states. LSMEM1 is associated with cell injury, inflammation and lipid metabolism. Further, LSMEM1 plays a critical role in delaying CKD progression through regulating lipid droplet accumulation in proximal tubular epithelial cells. This study explores the function of the small protein LSMEM1 in physiological and disease development. LSMEM1 may be a novel revenue for targeted therapy for CKD.

Keywords: LSMEM1; micropeptide; single cell RNA‐seqencing

DOI: https://doi.org/10.1002/advs.202507713

Sci Signal. 2025 Aug 26. 18(901): eadu7253

Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems.

Sangeevan Vellappan, Junhong Sun, John Favate, Pranavi Jagadeesan, Debbie Cerda, Premal Shah, Srujana S Yadavalli.

Bacterial small proteins (≤50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The Escherichia coli genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in E. coli during magnesium (Mg2+) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg2+ homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg2+ conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg2+ limitation independently of yoaI transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest that these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.

DOI: https://doi.org/10.1126/scisignal.adu7253

Front RNA Res. 2025 ;pii: 1555885. [Epub ahead of print]3

Identification of long noncoding RNAs (lncRNAs) and co-transcriptional analysis of mRNAs and lncRNAs in transcriptomes of Anopheles gambiae.

Jiannong Xu, Kai Hu, Michelle M Riehle, Vedbar S Khadka.

Anopheles gambiae is a primary malaria vector mosquito in Africa. RNA-seq based transcriptome analysis has been widely used to study gene expressions underlying mosquito life traits such as development, reproduction, immunity, metabolism, and behavior. While it is widely appreciated that long non-coding RNAs (lncRNAs) are expressed ubiquitously in transcriptomes across metazoans, lncRNAs remain relatively underexplored in An. gambiae, including their identity, expression profiles, and biological functions. The lncRNA genes were poorly annotated in the current reference of the PEST genome of An. gambiae. In this study, a set of publicly available RNA-seq datasets was leveraged to identify lncRNAs across diverse contexts, including whole mosquitoes, mosquito cells or tissues including hemocytes, midguts, and salivary glands, as well as under different physiological conditions including sugar-feeding, blood-feeding, bacterial challenges, and Plasmodium infections. A Transcript Discovery module implemented in CLC genomics workbench was used to identify lncRNAs from selected published RNA-seq datasets. Across this pool of transcriptomes, 2684 unique lncRNA genes, comprising 4082 transcripts, were identified. Following their identification, these lncRNA genes were integrated into the mosquito transcriptome annotation, which was then used as a reference to analyze both mRNAs and lncRNAs for transcriptional dynamics in different conditions. Unsurprisingly and similar to what has been reported for mRNAs, lncRNAs exhibited context-dependent expression patterns. Co-expression networks constructed using weighted gene co-expression network analysis (WGCNA) highlighted the interconnections among lncRNAs and mRNAs, which provides potential functional networks in which these lncRNAs are involved. Furthermore, we identified polysome-associated lncRNAs within polysome-captured transcripts, suggesting the involvement of lncRNAs in translation regulation and coding capacity for micropeptides. The analysis of a ChIP-seq dataset unveiled a correlation of transcriptional activities between lncRNAs and observed epigenetic signatures. Overall, our study demonstrated that lncRNAs are transcribed alongside mRNAs in various biological contexts. The genome-wide annotation of lncRNA genes and integration into the PEST reference genome enables the co-analysis of mRNA and lncRNA simultaneously, which will enhance our understanding of their functions, shedding light on their regulatory roles in An. gambiae biology.

Keywords: Anopheles gambiae; RNA-seq; long noncoding RNA (lncRNA); mosquitoes; transcriptome

DOI: https://doi.org/10.3389/frnar.2025.1555885