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Infiltrating macrophages have been proven as a pivotal pathological inflammatory cell subset in coxsackievirus B3 (CVB3) induced viral myocarditis. However, the mechanisms underlying the initiation and promotion of macrophage pro-inflammatory responses are still blur. We previously reported that cardiac ER stress contributed to CVB3-induced myocarditis by augmenting inflammation. In this study, we focused on the influence of ER stress on the macrophage inflammatory responses in the viral myocarditis. We found that ER stress was robustly induced in the cardiac infiltrating macrophages from CVB3-infected mice, and robustly facilitated the production of pro-inflammatory cytokines (IL-6, IL-12, MCP-1 and IP-10). Consistently, adoptive transfer of ER stressed macrophages significantly worsened the viral myocarditis; while transfer of ER stress-inhibited macrophages obviously alleviated the myocarditis. To our surprise, this significantly activated ER stress was not directly caused by the virus stimulation, but was transferred from the CVB3-infected, ER stressed myocardiocytes via soluble molecules in a TLR2, 4-independent way. In the present study, we reported that the transmissible ER stress from the infected myocardiocytes to macrophages could augment the pro-inflammatory responses and promoted the pathogenesis of viral myocarditis. Blocking ER stress transmission, instead of inhibiting its initiation, may represent novel therapeutic strategies against viral myocarditis.

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Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes ∼100 potential DUBs, which can be classified into six families, influencing multiple cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. To systematically explore the role of DUBs involved in antiviral immunity, we performed an RNA interference-based screening that contains 97 human DUBs. We identified that ubiquitin-specific protease (USP) 39 expression modulates the antiviral activity, which is, to our knowledge, a previously unknown function of this enzyme. Small interfering RNA knockdown of USP39 significantly enhanced viral replication, whereas overexpression of USP39 had an opposite effect. Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK/STAT downstream of type I signaling by enhancing IFN-stimulated response elements promoter activity and expression of IFN-stimulated genes. Interestingly, USP39, previously considered not to have the deubiquitinase activity, in this study is proved to interact with STAT1 and sustain its protein level by deubiqutination. Furthermore, we found that through novel mechanism USP39 can significantly decrease K6-linked but not K48-linked ubiquitination of STAT1 for degradation. Taken together, these findings uncover that USP39 is, to our knowledge, a new deubiquitinase that positively regulates IFN-induced antiviral efficacy.

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