PPM1B negatively regulates antiviral response via dephosphorylating TBK1

Abstract

The production of type I interferon must be tightly regulated and aberrant production of type I interferon is harmful or even fatal to the host. TBK1 phosphorylation at Ser172 plays an essential role in TBK1-mediated antiviral response. However, how TBK1 activity is negatively regulated remains poorly understood. Using a functional genomics approach, we have identified PPM1B as a TBK1 phosphatase. PPM1B dephosphorylates TBK1 in vivo and in vitro. PPM1B wild-type but not its phosphatase-deficient R179G mutant inhibits TBK1-mediated antiviral response and facilitates VSV replication in the cells. Viral infection induces association of PPM1B with TBK1 in a transient fashion in the cells. Conversely, suppression of PPM1B expression enhances virus-induced IRF3 phosphorylation and IFNβ production. Our study identifies a previously unrecognized role for PPM1B in the negative regulation of antiviral response by acting as a TBK1 phosphatase.

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

“…Thus, these studies indicate that SHP-2 and SHIP-1 inhibit TBK1 activation through other different mechanisms but not the direct dephosphorylation of TBK1. However, only PPM1B, a member of PP2C family, can interact with TBK1 and dephosphorylate TBK1 at Ser 172 in HEK293T cells and HeLa cells (17). In the present study, we provide the convincing evidence that PP4 functions as a novel TBK1 phosphatase to dephosphorylate TBK1 at Ser 172 and restrain the activation of TBK1 and downstream type I IFN signaling in macrophages and dendritic cells.…”

“…Although the roles of phosphatases, including tyrosine phosphatases and serine/threonine phosphatases, in the regulation of innate immune response draw more attention (35), only three phosphatases, SHP-2, SHIP-1, and PPM1B, have been found to control the activation of type I IFN signaling by acting on TBK1 until now (15)(16)(17). SHP-2 does not directly dephosphorylate TBK1 but suppresses TBK1 activity through a tyrosine phosphatase activity-independent mechanism to inhibit TRIF-dependent type I IFN and proinflammatory cytokine production (15).…”

“…However, how the kinase activity of TBK1 is switched off by its phosphatases remains poorly understood. Until now, there are three phosphatases that have been reported to negatively regulate type I IFN production by targeting TBK1 (15)(16)(17). Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibits TBK1 activity through a phosphatase activity-independent mechanism (15).…”

“…However, it is unlikely that SHP-2 and SHIP-1 function as TBK1 phosphatases to directly dephosphorylate and deactivate TBK1 (15,16). Only one serine/threonine phosphatase, protein phosphatase (PP) Mg 2+ /Mn 2+ -dependent 1B (PPM1B), is found to bind TBK1 and dephosphorylate TBK1 at Ser 172 , and then inhibit TBK1 activation in HEK293T cells and HeLa cells (17). However, whether other phosphatases also function in the direct regulation of phosphorylation and kinase activity of TBK1 in innate immune cells remains unknown, which needs to be further elucidated.…”

Casein Kinase II Controls TBK1/IRF3 Activation in IFN Response against Viral Infection

“…Conversely, disrupting the complex formation, ubiquitination, or phosphorylation of TBK1 can attenuate its activation. Deubiquitinase CYLD or USP2b can dampen TBK1 activation by removing the K63-type polyubiqutin chain (36,37), and protein phosphatase PPM1B may tamper TBK1 activity through dephosphorylation of S172 (38). Nevertheless, more mechanisms involved in the negative regulation of TBK1 remain to be identified.…”