2. Academic Validation
  3. Translation stress and collided ribosomes are co-activators of cGAS

Translation stress and collided ribosomes are co-activators of cGAS

  • Mol Cell. 2021 Jul 1;81(13):2808-2822.e10. doi: 10.1016/j.molcel.2021.05.018.
Li Wan 1,  Szymon Juszkiewicz 2,  Daniel Blears 3,  Prashanth Kumar Bajpe 1,  Zhong Han 3,  Peter Faull 4,  Richard Mitter 5,  Aengus Stewart 5,  Ambrosius P Snijders 4,  Ramanujan S Hegde 2,  Jesper Q Svejstrup 6
Affiliations

Affiliations

  • 1 Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 2 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
  • 3 Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Cellular and Molecular Medicine, Panum Institute, Blegdamsvej 3B, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 4 Protein Analysis and Proteomics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 5 Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 6 Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Cellular and Molecular Medicine, Panum Institute, Blegdamsvej 3B, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: jsvejstrup@sund.ku.dk.
PMID: 34111399 DOI: 10.1016/j.molcel.2021.05.018
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.

Keywords

ASCC3; IRF3; STING; ZNF598; cGAS; innate immunity; interferon signalling; mRNA translation; ribosome collision; ribosome-associated protein quality control.

Figures