Translation stress and collided ribosomes are co-activators of cGAS
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Li Wan Szymon Juszkiewicz Daniel Blears Prashanth Kumar Bajpe Zhong Han Peter Faull Richard Mitter Aengus Stewart Bram Snijders Ramanujan S Hegde Jesper SvejstrupAbstract
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.
Journal details
Journal Molecular Cell
Volume 81
Issue number 13
Pages 2808-2822.e10
Available online
Publication date
Full text links
Publisher website (DOI) 10.1016/j.molcel.2021.05.018
Figshare View on figshare
Europe PubMed Central 34111399
Pubmed 34111399