TRIM11 Negatively Regulates IFNβ Production and Antiviral Activity by Targeting TBK1

Abstract

The innate immune response is a host defense mechanism against infection by viruses and bacteria. Type I interferons (IFNα/β) play a crucial role in innate immunity. If not tightly regulated under normal conditions and during immune responses, IFN production can become aberrant, leading to inflammatory and autoimmune diseases. In this study, we identified TRIM11 (tripartite motif containing 11) as a novel negative regulator of IFNβ production. Ectopic expression of TRIM11 decreased IFNβ promoter activity induced by poly (I:C) stimulation or overexpression of RIG-I (retinoic acid-inducible gene-I) signaling cascade components RIG-IN (constitutively active form of RIG-I), MAVS (mitochondrial antiviral signaling protein), or TBK1 (TANK-binding kinase-1). Conversely, TRIM11 knockdown enhanced IFNβ promoter activity induced by these stimuli. Moreover, TRIM11 overexpression inhibited the phosphorylation and dimerization of IRF3 and expression of IFNβ mRNA. By contrast, TRIM11 knockdown increased the IRF3 phosphorylation and IFNβ mRNA expression. We also found that TRIM11 and TBK1, a key kinase that phosphorylates IRF3 in the RIG-I pathway, interacted with each other through CC and CC2 domain, respectively. This interaction was enhanced in the presence of the TBK1 adaptor proteins, NAP1 (NF-κB activating kinase-associated protein-1), SINTBAD (similar to NAP1 TBK1 adaptor) or TANK (TRAF family member-associated NF-κB activator). Consistent with its inhibitory role in RIG-I-mediated IFNβ signaling, TRIM11 overexpression enhanced viral infectivity, whereas TRIM11 knockdown produced the opposite effect. Collectively, our results suggest that TRIM11 inhibits RIG-I-mediated IFNβ production by targeting the TBK1 signaling complex.

TRIMmunity: The Roles of the TRIM E3-Ubiquitin Ligase Family in Innate Antiviral Immunity

“…Many TRIMs have been found to play negative regulatory roles in immune signaling. In most cases this is consistent with mechanisms involving ubiquitin-dependent degradation of targeted proteins, although not all of them act by proteasome-dependent mechanisms (TRIM11/21/27/30/38/59; Summarized in Figure 7) [40], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155] and [156]. …”

Grouper TRIM13 exerts negative regulation of antiviral immune response against nodavirus

“…Moreover, the N-terminal RING domain were always required for the antiviral activity of EcTRIM56 [26,27]. In contrast, overexpression of TRIM38 or TRIM11 in vitro resulted in enhanced replication of VSV [28,29]. In our study, the ectopic expression of EcTRIM13 significantly enhanced RGNNV replication, evidenced by the increase of CPE progression and viral gene transcription.…”

“…Based on the regulatory effects of TRIM proteins on virus replication, further studies explored the multiple molecular mechanisms underlying the interaction between TRIM proteins and other signaling molecules or their downstream events [6,27,29,30]. Ectopic expression of TRIM11 decreased IFNb promoter activity induced by the overexpression of RIG-I, mitochondrial antiviral signaling protein (MAVS), or TANK-binding kinase-1 (TBK1).…”

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

“…Viral-infection-induced immune response via pattern recognition receptors (PRRs) (TLRs and RIG-I-like receptors) (41,42) leads to activation of transcription factors, such as NF-B and IRFs, resulting in induction of proinflammatory cytokines and IFNs (43). The signaling cascade downstream of RIG-I includes activation of the IKK-related kinase IKK␣/␤ and TBK-1, resulting in phosphorylation of IRFs (IRF3 and IRF7).…”