Translation stress and collided ribosomes are co-activators of cGAS

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.

Automated summary

The cGAS-STING pathway can sense not only cytosolic DNA, but also dysfunctional protein production through interaction with purified ribosomes. Disruption of the ribosome-associated protein quality control pathway leads to cGAS-dependent ISG expression and sub-cellular re-localization, indicating a potent increase in cGAS activation under translation stress. These findings have implications for the inflammatory response to viral infection and tumorigenesis where cellular protein synthesis is substantially reprogrammed.