Abstract
Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49-/- mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49+/+ mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation.
Highlights
The innate immune system is the first line of defense against invading pathogens and innate immune response to microbial species is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by germline-encoded pattern-recognition receptors (PRRs)[1]
We have discovered that the deubiquitinating enzyme USP49 interacts with and removes K63-linked polyubiquitin chains from Mediator of IRF3 activation (MITA) to downregulate antiviral signaling
Structural and biochemical studies demonstrate that MITA is activated by binding to cyclic dinucleotides such as cyclic di-GMP which is generated by invading bacteria and cyclic GMP-AMP which is generated by cGAMP synthase upon binding to cytoplasmic DNA either from invading DNA viruses and retroviruses or from selfdamaged genomic or mitochondrial DNA [11,12,13,14,15,16,17,18]
Summary
The innate immune system is the first line of defense against invading pathogens and innate immune response to microbial species is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by germline-encoded pattern-recognition receptors (PRRs)[1]. Upon binding to the PAMPs, these PRRs recruit adaptor proteins or catalyze second messenger molecules for adaptor proteins activation, trigger a series of signaling cascades and eventually induce expression of an array of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines to elicit antiviral immune responses. Mediator of IRF3 activation (MITA, known as STING and ERIS) is an adaptor protein essential for cytoplasmic DNA-triggered signaling and host defense against HSV-1 and Listeria monocytogenes [6,7,8,9,10]. Several studies have shown that an array of cytoplasmic DNA sensors such as DAI, IFI16 and DDX41 directly recruit and activate MITA in a ligand and/or cell-type specific manner and the mechanisms are less clear [19,20,21]. Activated IRF3 and NF-κB enter nucleus to initiate transcription of a large number of downstream genes
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