USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA

Abstract

Mediator of IRF3 activation ([MITA] also known as STING) is a direct sensor of cyclic dinucleotide and critically mediates cytoplasmic DNA-triggered innate immune signaling. The activity of MITA is extensively regulated by ubiquitination and deubiquitination. In this study, we report that USP20 interacts with and removes K48-linked ubiquitin chains from MITA after HSV-1 infection, thereby stabilizing MITA and promoting cellular antiviral responses. Deletion of USP20 accelerates HSV-1-induced degradation of MITA and impairs phosphorylation of IRF3 and IkBa as well as subsequent induction of type I IFNs and proinflammatory cytokines after HSV-1 infection or cytoplasmic DNA challenge. Consistently, Usp20 2/2 mice produce decreased type I IFNs and proinflammatory cytokines, exhibit increased susceptibility to lethal HSV-1 infection, and aggravated HSV-1 replication compared with Usp20 +/+ mice. In addition, complement of MITA into Usp20 2/2 cells fully restores HSV-1-triggered signaling and inhibits HSV-1 infection. These findings suggest a crucial role of USP20 in maintaining the stability of MITA and promoting innate antiviral signaling.

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

“…Eight-week-old male and female KP, KP7 or KL mice were intranasally injected with Ad-Cre followed by various Quantitative real-time PCR. These experiments were performed as previously described 54,55 . Total RNA was extracted from tumor or normal tissues or cells using TRIzol reagent (Invitrogen), and the first-strand cDNA was reversedtranscribed with All-in-One cDNA Synthesis SuperMix (Biotool).…”

USP44 positively regulates innate immune response to DNA viruses through deubiquitinating MITA

“…Previously, it has been demonstrated that USP13 removes K27-linked polyubiquitin chains from MITA and impairs its recruitment of TBK1, contributing to inhibition of innate immune response to DNA viruses [36]. It has also been reported that USP20 deconjugates K33-and K48-linked polyubiquitin chains from MITA thus maintains its stability [48,50]. Interestingly, USP20 has also been shown to deubiquitinate and stabilize ULK1 which is a negative regulator of MITA [51,52].…”

“…It has been reported that the deubiquitin enzymes USP20 and CYLD could remove K48-linked polyubiquitin moieties from MITA [48,49]. Therefore, we further investigated the relevance of USP44, USP20 and CYLD in their regulation of MITA-mediated signaling.…”

The interactions between cGAS-STING pathway and pathogens

“…This modification triggers STING degradation through the proteasome pathway and diminishes downstream antiviral signalling. 103,104 Conversely, the K48-linked polyubiquitination of STING is reversed by various DUBs, including CYLD, USP20 and eukaryotic translation initiation factor 3 subunit 5 (EIF3S5) [105][106][107] (Table 1). Therefore, the subtle balance between the levels of E3 ligase and DUBs regulates the active cGAS-STING pathway.…”