bims-micpro 2024-04-21 papers

Cell Rep. 2024 Apr 15. pii: S2211-1247(24)00402-9. [Epub ahead of print]43(4): 114074

UPF1 regulates mRNA stability by sensing poorly translated coding sequences.

Damir Musaev, Mario Abdelmessih, Charles E Vejnar, Valeria Yartseva, Linnea A Weiss, Ethan C Strayer, Carter M Takacs, Antonio J Giraldez.

Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay. We find that Upf1 binds poorly translated and untranslated ORFs, which are associated with a higher decay rate, including mRNAs with uORFs and those with exposed ORFs after stop codons. Our study emphasizes Upf1's converging role in surveilling mRNAs with exposed ORFs that are poorly translated, such as mRNAs with long ORFs, ORF-like 3' UTRs, and mRNAs containing uORFs. We propose that Upf1 regulation of poorly/untranslated ORFs provides a unifying mechanism of surveillance in regulating mRNA stability and homeostasis in an exon-junction complex (EJC)-independent nonsense-mediated decay (NMD) pathway that we term ORF-mediated decay (OMD).

Keywords: CP: Molecular biology; GC-richness; NMD; ORF length; UPF1; mRNA decay; mRNA homeostasis; mRNA translation; oORF; uORF

DOI: https://doi.org/10.1016/j.celrep.2024.114074

Cancer Cell Int. 2024 Apr 15. 24(1): 134

Micropeptides: potential treatment strategies for cancer.

He Zhou, Yan Wu, Ji Cai, Dan Zhang, Dongfeng Lan, Xiaofang Dai, Songpo Liu, Tao Song, Xianyao Wang, Qinghong Kong, Zhixu He, Jun Tan, Jidong Zhang.

Some noncoding RNAs (ncRNAs) carry open reading frames (ORFs) that can be translated into micropeptides, although noncoding RNAs (ncRNAs) have been previously assumed to constitute a class of RNA transcripts without coding capacity. Furthermore, recent studies have revealed that ncRNA-derived micropeptides exhibit regulatory functions in the development of many tumours. Although some of these micropeptides inhibit tumour growth, others promote it. Understanding the role of ncRNA-encoded micropeptides in cancer poses new challenges for cancer research, but also offers promising prospects for cancer therapy. In this review, we summarize the types of ncRNAs that can encode micropeptides, highlighting recent technical developments that have made it easier to research micropeptides, such as ribosome analysis, mass spectrometry, bioinformatics methods, and CRISPR/Cas9. Furthermore, based on the distribution of micropeptides in different subcellular locations, we explain the biological functions of micropeptides in different human cancers and discuss their underestimated potential as diagnostic biomarkers and anticancer therapeutic targets in clinical applications, information that may contribute to the discovery and development of new micropeptide-based tools for early diagnosis and anticancer drug development.

Keywords: Cancer; Micropeptide; Noncoding RNAs; Subcellular localization

DOI: https://doi.org/10.1186/s12935-024-03281-w

J Clin Invest. 2024 Apr 16. pii: e178392. [Epub ahead of print]

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-β1-induced fibrotic responses in renal fibroblasts and epithelial cells independent of Smad3 phosphorylation. Cellular uptake of Cf48 and its pro-fibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'-untranslated region of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis which operates as an RNA-binding peptide to promote the production of extracellular matrix.

Keywords: Fibrosis; Nephrology

DOI: https://doi.org/10.1172/JCI178392