Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L
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Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L. / Xi, Jiajia; Snieckute, Goda; Martínez, José Francisco; Arendrup, Frederic Schrøder Wenzel; Asthana, Abhishek; Gaughan, Christina; Lund, Anders H.; Bekker-Jensen, Simon; Silverman, Robert H.
In: Cell Reports, Vol. 43, No. 4, 113998, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 387507268