Negative Regulation of MAVS-Mediated Innate Immune Response by PSMA7

Abstract

Innate immunity to viruses involves receptors such as Retinoic Acid Induced Gene-1 (RIG-I), which senses viral RNA and triggers a signaling pathway involving the outer mitochondrial membrane protein mitochondrial antiviral signaling (MAVS). Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial antiviral immunity. In this study, we demonstrate that the proteasome PSMA7 (α4) subunit associates with MAVS in vivo and in vitro. Expression of PSMA7 results in a potent inhibition of RIG-1 and MAVS-mediated IFN-β promoter activity; conversely, depletion of PSMA7 with small interference RNA enhances virus-induced type I IFN production, with consequent reduction of virus replication. Furthermore, a striking reduction in the abundance of endogenous MAVS with overexpressed PSMA7 was found and virus infection leads to transient increase in the endogenous PSMA7 protein level. Cumulatively, these results suggest that PSMA7 is a negative regulator of the MAVS-mediated innate immunity that probably serves to attenuate the establishment of an antiviral state during viral infection, highlighting the biological significance of PSMA7-MAVS association as an important cellular regulatory control.

USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors

“…For example, NLRC5 and NLRX1 directly interact with RIG-I/MDA5 or MAVS to inhibit type I IFN signaling pathway [25][26][27][28]. PSMA7 and PCBP2/AIP4 inhibit type I IFN signaling by targeting MAVS for ubiquitination and degradation [29,30]. Similarly, NLRP4 inhibits type I IFN signaling by targeting TBK1 for ubiquitination and degradation via a ubiquitin E3 ligase DTX4 [31].…”

Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

“…Besides, PCBP1 displays some regulatory effects after viral infection ( Figures 3D and 6). In either case, the engagement of PCBP1 is crucial because of one thing, effective suppression of IFN-α/β may only be possible with the concerted actions of several suppressors, and for the other, unlike those stimulus-triggered inhibitors including PCBP2 [6,22,35,[47][48][49][50][51][52][53], PCBP1 may serve to tune the threshold for initiation of signal transduction by restricting MAVS at basal conditions [54,55]. The latter feature of PCBP1 is of special importance in preventing various inflammatory disorders caused by unwanted IFN [33,[56][57][58] as a result of possible activities of excessive MAVS.…”

“…A tight MAVS regulation is essential to prevent unwarranted responses or even inflammation [33]. The regulation occurs at various levels ranging from complex formation to posttranslational modifications [34], among which ubiquitination and degradation by the proteasome pathway have been frequently reported [22,29,35,36].…”

An Alternative Splicing Isoform of MITA Antagonizes MITA-Mediated Induction of Type I IFNs

“…Several molecules, such as dihydroxyacetone kinase (23), suppressor of IKBKE (24), NLR family member X1) (25), and proteasome subunit a type 7 (26), have been identified as negative regulators in innate immune signaling pathways. In the case of MITA, it has been reported that as the E3 ligase, RNF5 targets MITA for ubiquitination and degradation.…”