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Translation stress and collided ribosomes are co-activators of cGAS

  • Li Wan
    ,
  • Szymon Juszkiewicz
    ,
  • Daniel Blears
    ,
  • Prashanth Bajpe
    ,
  • Zhong Han
    ,
  • Peter Faull
  • The Francis Crick Institute
    ,
  • Medical Research Council
    ,
  • University of Copenhagen
Research Output: Contribution to journal Article Peer-review

Open access

Abstract

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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 2808-2822

Journal (Volume, Issue Number)

Molecular Cell (Volume 81, Issue 13)

Publication milestones

  • Accepted/In press - 13/05/2021
  • Published - 01/07/2021

Publication status

Published - 01/07/2021

ISSN

1097-2765

External Publication IDs

  • handle.net: 10547/626251
  • Scopus: 85111132535
  • PubMed: 34111399

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