Research Article: The deubiquitinase CYLD is a specific checkpoint of the STING antiviral signaling pathway

Date Published: November 2, 2018

Publisher: Public Library of Science

Author(s): Lele Zhang, Ning Wei, Ye Cui, Ze Hong, Xing Liu, Qiang Wang, Senlin Li, Heng Liu, Huansha Yu, Yanni Cai, Quanyi Wang, Juanjuan Zhu, Wei Meng, Zhengjun Chen, Chen Wang, Edward Mocarski.

http://doi.org/10.1371/journal.ppat.1007435

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.

Partial Text

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].

As the convergence point for monitoring cytosolic aberrant DNAs, STING integrates upstream danger signals to activate TBK1/IRF3, which ultimately induces the production of type I IFNs and proinflammatory cytokines [38]. However, misregulation of STING signaling has been implicated in cancers and autoimmune diseases. Thus, the strength and duration of STING signaling are dynamically modulated in a multilayered and highly ordered manner to maintain immune homeostasis. It is well established that modification of STING by different types of polyubiquitin chains serves to fine-tune STING activity in response to extracellular and intracellular stresses [16]. Similarly, removing polyubiquitin chains from STING acted as an effective feedback mechanism to counterbalance the relevant immune responses. A recent report demonstrated that USP13 could remove K27-linked polyubiquitin chains from STING, thus downregulating STING signaling [39]. It remains unknown how other types of STING polyubiquitination are terminated and how STING activity is sustained during viral infection.

 

Source:

http://doi.org/10.1371/journal.ppat.1007435

 

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