IGHMBP2 deletion suppresses translation and activates the integrated stress response.

Autor:	Park JE; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143.; Tetrad Graduate Program, University of California, San Francisco, San Francisco, California, USA, 94143., Desai H; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143., Liboy-Lugo J; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143.; Tetrad Graduate Program, University of California, San Francisco, San Francisco, California, USA, 94143., Gu S; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143., Jowhar Z; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California, USA, 94143., Xu A; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California, USA, 94143., Floor SN; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA, 94143.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA, 94143.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 12. Date of Electronic Publication: 2023 Dec 12.
DOI:	10.1101/2023.12.11.571166
Abstrakt:	IGHMBP2 is a non-essential, superfamily 1 DNA/RNA helicase that is mutated in patients with rare neuromuscular diseases SMARD1 and CMT2S. IGHMBP2 is implicated in translational and transcriptional regulation via biochemical association with ribosomal proteins, pre-rRNA processing factors, and tRNA-related species. To uncover the cellular consequences of perturbing IGHMBP2, we generated full and partial IGHMBP2 deletion K562 cell lines. Using polysome profiling and a nascent protein synthesis assay, we found that IGHMBP2 deletion modestly reduces global translation. We performed Ribo-seq and RNA-seq and identified diverse gene expression changes due to IGHMBP2 deletion, including ATF4 upregulation. With recent studies showing the ISR can contribute to tRNA metabolism-linked neuropathies, we asked whether perturbing IGHMBP2 promotes ISR activation. We generated ATF4 reporter cell lines and found IGHMBP2 knockout cells demonstrate basal, chronic ISR activation. Our work expands upon the impact of IGHMBP2 in translation and elucidates molecular mechanisms that may link mutant IGHMBP2 to severe clinical phenotypes. Competing Interests: COMPETING INTEREST STATEMENT The authors declare no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu