Translation stress and collided ribosomes are co-activators of cGAS

Li Wan,Szymon Juszkiewicz,Daniel Blears,Prashanth Kumar Bajpe,Zhong Han,Peter Faull,Richard Mitter,Aengus Stewart,Ambrosius P Snijders,Ramanujan S Hegde,Jesper Q Svejstrup

doi:10.1016/j.molcel.2021.05.018

Abstract

SummaryThe 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.

Highlights

In the innate immune system, pattern recognition receptors recognize both self and nonself features to activate signaling pathways that lead to the production of interferons (IFNs) and proinflammatory cytokines (Takeuchi and Akira, 2010; Brubaker et al, 2015; Tan et al, 2018)
Ribosome quality control and cyclic GMP-AMP synthase (cGAS)-dependent activation of interferon-stimulated genes (ISGs) Our previous findings, as well as those of others, indicated that ASCC3 deficiency leads to activation of ISGs (Li et al, 2013; Williamson et al, 2017), a characteristic of the innate immune response
ASCC3 has been shown to have a separate role in the cytosol where it participates in the ribosome-associated protein quality control (RQC) pathway, the disassembly of collided ribosomes (Hashimoto et al, 2020; Juszkiewicz et al, 2020)

Summary

Introduction

In the innate immune system, pattern recognition receptors recognize both self and nonself features to activate signaling pathways that lead to the production of interferons (IFNs) and proinflammatory cytokines (Takeuchi and Akira, 2010; Brubaker et al, 2015; Tan et al, 2018). An important enzyme in this system, cyclic GMP-AMP synthase (cGAS), is activated by both cytosolic self-DNA and pathogen-derived DNA. CGAS synthesizes 20-3-cyclic GMP-AMP (cGAMP) (Ablasser et al, 2013a; Gao et al, 2013; Sun et al, 2013; Zhang et al, 2013), which functions as a second messenger that is bound by stimulator of interferon genes (STING). Phosphorylated IRF3 dimerizes and translocates into the nucleus to activate type I interferon (IFN) and interferon-stimulated genes (ISGs) (Chen et al, 2016; Kato et al, 2017; Ablasser and Chen, 2019; Hopfner and Hornung, 2020)

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