Abstract
TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. Here we show human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNβ in the lung. We find that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellular calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNβ induction in an RyR-dependent manner. This study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury.
Highlights
Tripartite motif-containing (TRIM) family proteins play integral roles in the innate immune response to virus infection
We demonstrate that knockdown of mitsugumin 53 (MG53) results in aberrant macrophage calcium handling, and that suppression of IFNβ transcription by MG53 is dependent on ryanodine receptor (RyR)-mediated calcium signaling
Seeing that MG53 is a PRY-SPRY-containing TRIM protein involved in tissue repair, we sought to investigate whether MG53 is endogenously expressed in monocytes/macrophages
Summary
TRIM family proteins play integral roles in the innate immune response to virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. Tissue repair in response to infection or injury is mediated by numerous different cell types. Type I interferons (IFNs) are among the most important cytokines produced by inflammatory macrophages in response to viral infection and tissue injury. While several studies have reported the expression of ryanodine receptor (RyR) calcium channels in macrophages[9,10], the physiological role of RyR in immune regulation has yet to be fully characterized. Tripartite motif-containing (TRIM) family proteins participate in the regulation of numerous physiological processes, including immunity[11]. Several TRIM proteins are known to be regulated by viral infection and IFN12,13, and many TRIM proteins participate in the control of viral immunity[14]. Studies utilizing exogenous recombinant human MG53 (rhMG53) have shown protective effects against both mechanical injury and oxidative stress[15,18,19,20,21]
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