Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Abstract

The effective recognition of viral infection and subsequent type I IFN production is essential for the host antiviral innate immune responses. The phosphorylation and activation of kinase TANK-binding kinase 1 (TBK1) plays crucial roles in the production of type I IFN mediated by TLR and retinoic acid–inducible gene I–like receptors. Type I IFN expression must be tightly regulated to prevent the development of immunopathological disorders. However, how the activated TBK1 is negatively regulated by phosphatases remains poorly understood. In this study, we identified a previously unknown role of protein phosphatase (PP)4 by acting as a TBK1 phosphatase. PP4 expression was upregulated in macrophages infected with RNA virus, vesicular stomatitis virus, and Sendai virus in vitro and in vivo. Knockdown of PP4C, the catalytic subunit of PP4, significantly increased type I IFN production in macrophages and dentritic cells triggered by TLR3/4 ligands, vesicular stomatitis virus, and Sendai virus, and thus inhibited virus replication. Similar results were also found in peritoneal macrophages with PP4C silencing in vivo and i.p. infection of RNA virus. Accordingly, ectopic expression of PP4C inhibited virus-induced type I IFN production and promoted virus replication. However, overexpression of a phosphatase-dead PP4C mutant abolished the inhibitory effects of wild-type PP4C on type I IFN production. Mechanistically, PP4 directly bound TBK1 upon virus infection, then dephosphorylated TBK1 at Ser172 and inhibited TBK1 activation, and subsequently restrained IFN regulatory factor 3 activation, resulting in suppressed production of type I IFN and IFN-stimulated genes. Thus, serine/threonine phosphatase PP4 functions as a novel feedback negative regulator of RNA virus-triggered innate immunity.

USP7‐TRIM27 axis negatively modulates antiviral type I IFN signaling

“…(28,30,(57)(58)(59)(60)(61)(62). For instance, protein phosphatase, Mg2 + /Mn2 + -dependent 1A and 1B, protein phosphatase 4, Raf kinase inhibitor protein, glycogen synthase kinase-3b, and glucocorticoids have been reported to modulate TBK1 activity through phosphorylation and dephosphorylation (63)(64)(65)(66)(67). The K63-linked polyubiquitination of TBK1 is associated with enhanced TBK1 activity and type I IFN signaling, The ubiquitin E3 ligases TRAF, mind bomb 1 and 2, neuregulin receptor degradation protein-1, and ring finger protein-128 promote the K63-linked polyubiquitination of TBK1 and boost the innate immune response (62,(68)(69)(70).…”

Intrahepatic Toll-Like Receptor 3 in Chronic HBV Infection Subjects: Asymptomatic Carriers, Active Chronic Hepatitis, Cirrhosis, and Hepatocellular Carcinoma

“…Previous research studied feedback regulation in TLRs signaling pathways, in which positive/negative feedback regulation controlled the expression of up/down-stream factors and regulated immune and inflammatory reactions (21-23). Imaizumi et al found that the positive feedback of IFN-stimulated gene56 regulated the expression of IFN-stimulated gene54 in the TLR3/IFN-β signaling pathway (23).…”

Protein phosphatase 4 coordinates glial membrane recruitment and phagocytic clearance of degenerating axons in Drosophila

“…The serine/threonine PP4 complex was recently identified as a requisite factor for proper immune responses in T cells, B cells, and macrophages, 40, 41, 42 including proliferation and immune gene induction. Although the specific role of PP4 in glial cell immunity has not been investigated, increased PP4 expression has been reported in glial tumors, suggesting a connection between PP4 function and glial cell invasiveness.…”