Abstract
Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.
Highlights
The innate immune system represents the first line of host defense against invading pathogens and employs germline-encoded pattern-recognition receptors (PRRs) to detect conserved microbial molecules known as pathogen-associated molecular patterns (PAMPs)
It is well established that covalent modification of Stimulator of interferon genes (STING) by different types of polyubiquitin chains serves to fine-tune STING activity in response to extracellular and intracellular stresses
We characterized the deubiquitinase CYLD, which partially accumulates with STING upon HSV-1 infection and interacts selectively with the K48-linked
Summary
The innate immune system represents the first line of host defense against invading pathogens and employs germline-encoded pattern-recognition receptors (PRRs) to detect conserved microbial molecules known as pathogen-associated molecular patterns (PAMPs). Upon sensing their corresponding PAMPs, PRRs activate signaling cascades that trigger the expression of downstream genes, which collaboratively restrain microbes and activate adaptive immune responses [1]. The signaling pathways triggered by these sensors all converge at stimulator of interferon genes (STING, known as MITA, ERIS or MPYS), an endoplasmic reticulum (ER) protein [12,13,14,15] that recruits and activates TBK1 and IKK to induce the expression of antiviral and proinflammatory genes. It remains largely unknown how polyubiquitin chains on STING are dynamically removed in response to different stimuli
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