open access publication

Article, 2024

Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L

Cell Reports, ISSN 2639-1856, 2211-1247, Volume 43, 4, Page 113998, 10.1016/j.celrep.2024.113998

Contributors

Xi, Jiajia (Corresponding author) [1] Snieckute, Goda 0000-0003-0738-0926 [2] Martínez, José Francisco 0000-0002-3457-2088 [2] Arendrup, Frederic Schrøder Wenzel 0000-0001-6488-4616 [2] Asthana, Abhishek 0000-0002-5429-6199 [1] Gaughan, Christina 0000-0002-0869-9026 [1] Lund, Anders Henrik 0000-0002-7407-3398 [2] Bekker-Jensen, Simon Holst 0000-0002-7308-4597 (Corresponding author) [2] Silverman, Robert H 0000-0003-2432-992X (Corresponding author) [1]

Affiliations

  1. [1] Cleveland Clinic
    2. [NORA names: United States; America, North; OECD];
  2. [2] University of Copenhagen
    3. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD]

Abstract

RNase L is an endoribonuclease of higher vertebrates that functions in antiviral innate immunity. Interferons induce oligoadenylate synthetase enzymes that sense double-stranded RNA of viral origin leading to the synthesis of 2',5'-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L remodels the host cell transcriptome. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A is directly introduced into cells. Here, we report that RNase L activation by 2-5A causes a ribotoxic stress response involving the MAP kinase kinase kinase (MAP3K) ZAKα, MAP2Ks, and the stress-activated protein kinases JNK and p38α. RNase L activation profoundly alters the transcriptome by widespread depletion of mRNAs associated with different cellular functions but also by JNK/p38α-stimulated induction of inflammatory genes. These results show that the 2-5A/RNase L system triggers a protein kinase cascade leading to proinflammatory signaling and apoptosis.

Keywords

JNK, L activity, MAP kinase kinase kinase, MAP2Ks, MAP3, MAP3K, RNA, RNase, RNase L, RNase L activity, RNase L., Zaka, activation of RNase L., activity, antiviral innate immunity, apoptosis, cascade, cell transcriptome, cells, cellular functions, depletion, double-stranded RNA, effect, effects of double-stranded RNA, endoribonuclease, enzyme, function, genes, higher vertebrates, host, host cell transcriptome, immunity, induction, induction of inflammatory genes, inflammatory genes, initiation, innate, innate immunity, interferon, isolation effect, kinase, kinase JNK, kinase cascade, kinase kinase, maps, oligoadenylate, oligoadenylate synthetase enzymes, origin, p38a, proinflammatory signaling, protein, protein kinase JNK, protein kinase cascade, response, results, ribotoxic stress response, sensing double-stranded RNA, signal, stress response, stress-activated protein kinase JNK, synthesis, synthetase enzymes, transcriptome, vertebrates, viral origin, virus

Funders

  • European Research Council
  • Danish National Research Foundation
  • National Institute of Allergy and Infectious Diseases
  • European Commission

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