TY - JOUR

T1 - Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L

AU - Xi, Jiajia

AU - Snieckute, Goda

AU - Martínez, José Francisco

AU - Arendrup, Frederic Schrøder Wenzel

AU - Asthana, Abhishek

AU - Gaughan, Christina

AU - Lund, Anders H.

AU - Bekker-Jensen, Simon

AU - Silverman, Robert H.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - 2-5A

KW - CP: Immunology

KW - innate immunity

KW - OAS

KW - ribotoxic stress response

KW - RNase L

KW - ZAKalpha

U2 - 10.1016/j.celrep.2024.113998

DO - 10.1016/j.celrep.2024.113998

M3 - Journal article

C2 - 38551960

AN - SCOPUS:85188961238

VL - 43

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 4

M1 - 113998

ER -