Translation stress and collided ribosomes are co-activators of cGAS
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Authors
Wan, LiJuszkiewicz, Szymon
Blears, Daniel
Bajpe, Prashanth Kumar
Han, Zhong
Faull, Peter
Mitter, Richard
Stewart, Aengus
Snijders, Ambrosius P.
Hegde, Ramanujan S.
Svejstrup, Jesper Q.
Issue Date
2021-07-01Subjects
ASCC3IRF3
STING
ZNF598
cGAS
innate immunity
interferon signalling
mRNA translation
ribosome collision
ribosome-associated protein quality control
Subject Categories::C760 Biomolecular Science
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The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to activate the innate immune system. Here, we report the unexpected discovery that cGAS also senses dysfunctional protein production. Purified ribosomes interact directly with cGAS and stimulate its DNA-dependent activity in vitro. Disruption of the ribosome-associated protein quality control (RQC) pathway, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and orthogonal perturbations that result in elevated levels of collided ribosomes and RQC activation cause sub-cellular re-localization of cGAS and ribosome binding in vivo as well. Thus, translation stress potently increases DNA-dependent cGAS activation. These findings have implications for the inflammatory response to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.Citation
Wan L, Juszkiewicz S, Blears D, Bajpe PK, Han Z, Faull P, Mitter R, Stewart A, Snijders AP, Hegde RS, Svejstrup JQ (2021) 'Translation stress and collided ribosomes are co-activators of cGAS', Molecular Cell, 81 (13), pp.2808-2822.Publisher
Cell PressJournal
Molecular CellPubMed ID
34111399PubMed Central ID
PMC8260207Additional Links
https://www.sciencedirect.com/science/article/pii/S1097276521004020Type
ArticleLanguage
enISSN
1097-2765EISSN
1097-4164Sponsors
This work was supported by the Francis Crick Institute (FCI receives funding from Cancer Research UK [FC001166], the UK Medical Research Council [FC001166], and the Wellcome Trust [FC001166]), grants to J.Q.S. from the European Research Council (Agreement 693327), a Laureate grant from the Novo Nordisk Foundation (NNF19OC0055875), and a Chair grant from the Danish National Research Foundation (DNRF153). Work in the Hegde lab was supported by the UK Medical Research Council (MC_UP_A022_1007 to R.S.H.). L.W. and Z.H. were supported by the EMBO-LTF program (EMBO ALTF 1071-2015 and EMBO ALTF 5-2019, respectively).ae974a485f413a2113503eed53cd6c53
10.1016/j.molcel.2021.05.018
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