Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Cell Rep. 2024 Jun 25;43(6):114287. doi: 10.1016/j.celrep.2024.114287.

Agnes Karasik ¹, Hernan A Lorenzi ², Andrew V DePass ¹, Nicholas R Guydosh ³

Affiliations

1 Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2 TriLab Bioinformatics Group, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3 Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

PMID: 38823018 DOI: 10.1016/j.celrep.2024.114287

Abstract

Viral Infection triggers several double-stranded RNA (dsRNA) sensors that lead to changes in gene expression in the cell. One of these sensors activates an Endonuclease, ribonuclease L (RNase L), that cleaves single-stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here, we show that this fragmentation induces the ribotoxic stress response via ZAKα, potentially through stalled ribosomes and/or ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes. Intriguingly, we found that the activity of the generic Endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an Antiviral program.

Keywords

CP: Immunology; CP: Molecular biology; RNase A; RNase L; ZAKα; endonuclease; integrated stress response; ribosome collisions.

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