Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.

High-salt diets have recently been implicated in hypertension, cardiovascular disease, and autoimmune disease. However, whether and how dietary salt affects host antiviral response remain elusive. Here, we report that high salt induces an instant reduction in host antiviral immunity, although this effect is compromised during a long-term high-salt diet. Further studies reveal that high salt stimulates the acetylation at Lys663 of p97, which promotes the recruitment of ubiquitinated proteins for proteasome-dependent degradation. p97-mediated degradation of the deubiquitinase USP33 results in a deficiency of Viperin protein expression during viral infection, which substantially attenuates host antiviral ability. Importantly, switching to a low-salt diet during viral infection significantly enhances Viperin expression and improves host antiviral ability. These findings uncover dietary saltinduced regulation of ubiquitinated cellular proteins and host antiviral immunity, and could offer insight into the daily consumption of salt-containing diets during virus epidemics.

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Rheumatoid arthritis (RA) is an autoimmune disease with nearly 1.6 billion patients worldwide and an incidence of 0.5−1%. In recent years, basic and clinical studies have revealed that immune cell responses and corresponding secretion of inflammatory factors are important in the control of RA development. Our study found that a natural plant ingredient, menthone, could be used as a potential antirheumatism compound. In vivo observations demonstrated that menthone alleviates collagen II-induced arthritis (CIA) in mice. Furthermore, we found that menthone regulates the number of Th1 and Th17 cells in CIA mice. Importantly, menthone significantly inhibits the release of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, in CIA mice. Our study suggests a potential component for the development of drugs to treat rheumatoid arthritis.

Type I interferon (IFN‐I) is a common biological molecule used for the treatment of viral diseases. However, the clinical antiviral efficacy of IFN‐I needs to be greatly improved. In this study, IFN‐I receptor 2 (IFNAR2) was revealed to undergo degradation at the protein level in cells treated with IFN‐I for long periods of time. Further studies found a physical interaction between the E3 ubiquitin ligase midline‐1 (MID1) and IFNAR2. As a consequence, MID1 induced both K48‐ and K63‐linked polyubiquitination of IFNAR2, which promoted IFNAR2 protein degradation in a lysosome‐dependent manner. Conversely, knockdown of MID1 largely restricted IFN‐I‐induced degradation of IFNAR2. Importantly, MID1 regulated the strength of IFN‐I signalling and IFN‐I‐induced antiviral activity. These findings reveal a regulatory mechanism of IFNAR2 ubiquitination and protein stability in IFN‐I signalling, which could provide a potential target for improving the antiviral efficacy of IFN‐I.