TRIM21 Restricts Coxsackievirus B3 Replication, Cardiac and Pancreatic Injury via Interacting With MAVS and Positively Regulating IRF3-Mediated Type-I Interferon Production

Abstract

Tripartite motif-containing 21 (TRIM21) is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in negative regulation of IRF3-dependent type I interferon signaling. However, the antiviral activity of TRIM21 varies among diverse viruses and its role on regulation of type I interferon remains inconsistent in different microbial infections. Here, we investigate the potential role for TRIM21 in controlling Coxsackievirus B3 (CVB3) replication and susceptible organ pathology. We found that CVB3 infection up-regulated the expression of TRIM21 in hearts of mice and cardiomyocytes at early phase of infection. Knock-down of TRIM21 resulted in increased viral replication, while overexpression led to increased phosphorylation and dimerization of IRF3, increased IFN-β transcription and reduced viral replication in vitro. We demonstrate that TRIM21 promotes the activation of IRF3 in CVB3-infected cells via interacting with MAVS and catalyzing the K27-linked polyubiquitination of MAVS, thereby enhancing type I interferon signaling. The RING domain of ubiquitin ligase activity and PRY-SPRY domain of TRIM21 are critical for its anti-viral effect. In vivo overexpression of TRIM21 significantly protected mice against viral myocarditis by suppressing CVB3 replication and reducing cardiac inflammatory cytokine production. While TRIM21 deficient mice exhibited a decreased IFN-β production, an increased cardiac and pancreatic CVB3 replication, and aggravated pancreatic injury as well as myocarditis during acute infection. Thus, our results demonstrate TRIM21 as a positive regulator of IFN-β signaling by targeting MAVS during CVB3 infection and suggest it as a potent host defense against CVB3 infection and viral-induced injury in hearts and pancreas.

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…Aside from the prototypical K63 and K48 ubiquitin linkages, other chain types can also be critical in certain situations. For example, in addition to its role in autophagy, K27-linked polyubiquitin mediates the recruitment of MAVS to TBK1, leading to IRF3 activation and IFN-I production in response to viral infection [95,96]. Upon infection with several viruses including HCV, Newcastle disease virus (NDV), SeV, VSV and Coxsackie virus B3 (CVB3), TRIM21 is expressed and interacts with MAVS through its PRY-SPRY domain.…”

“…Upon infection with several viruses including HCV, Newcastle disease virus (NDV), SeV, VSV and Coxsackie virus B3 (CVB3), TRIM21 is expressed and interacts with MAVS through its PRY-SPRY domain. This association allows for the conjugation of K27-linked polyubiquitin onto the K325 residue of MAVS for downstream signalling [95,96].…”

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

“…In fact, consistently elevated IL-6 levels were observed in an EV-A71 infection neonatal mouse model resulting in severe damage to numerous organs including the brain (Khong et al, 2012) pointing to EV infected astrocytes as contributors to CNS damage. Indeed, previous studies found elevated levels of IL-6 and IL-8 in CSF of EV-A71 positive patients with encephalitis or meningoencephalitis Liu et al, 2018) and expression of these cytokines may be due to viral infected astrocytes. In one study, CVB3 infection of astrocytoma cells resulted in a productive but non-cytopathic infection that could contribute to viral persistence in vivo within the CNS.…”

“…Other enteroviruses including CVB1, CVB5, EV-A71 and CVA16 induced type I IFNs through activation of TLR7 (Chehadeh and Alkhabbaz, 2013;Song et al, 2018). Further study of CVB3 infection revealed the upregulation of TRIM21, an intracellular protein that directs virions for degradation, which was necessary in mediating type I IFN (IFNβ) antiviral response through IRF3 (Liu et al, 2018). Viral spread to other tissues was observed in TRIM21 deficient mice, but the importance of this in terms of neuroinvasion remains unexplored (Liu et al, 2018).…”

“…Further study of CVB3 infection revealed the upregulation of TRIM21, an intracellular protein that directs virions for degradation, which was necessary in mediating type I IFN (IFNβ) antiviral response through IRF3 (Liu et al, 2018). Viral spread to other tissues was observed in TRIM21 deficient mice, but the importance of this in terms of neuroinvasion remains unexplored (Liu et al, 2018). Enteroviruses were also found to induce an antiviral state in neighboring, non-infected cells.…”