ABSTRACT
During virus infection, RIG-I-like receptors (RLRs) recognize viral RNAs and recruit the adaptor protein VISA to activate downstream signaling, leading to activation of transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs). IFNs further induce expression of hundreds of IFN-stimulated genes (ISGs) that suppress viral replication and facilitate the adaptive immune response. Dysregulated production of IFNs is implicated in various immune diseases. Here we identified Signal Recognition Particle 54 (SRP54) as a negative regulator of RLRs-induced antiviral signaling. Overexpression of SRP54 inhibited RNA virus-triggered induction of IFN-ß and increased viral replication, whereas knockdown of SRP54 had opposite effects. Mechanistically, SRP54 interacted with both RIG-I and MDA5 and impaired their association with VISA. Our findings demonstrate that SRP54 acts as a negative regulator of RLRs-mediated innate immune response by disrupting the recruitment of VISA to RIG-I/MDA5.
Subject(s)
Interferon Type I , Interferon-beta , Antiviral Agents , Gene Expression , Humans , Immunity, Innate , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/metabolism , Signal Recognition ParticleABSTRACT
Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.
Subject(s)
DNA Viruses/immunology , Immunity, Innate , Membrane Proteins/metabolism , Ubiquitin Thiolesterase/metabolism , Animals , Deubiquitinating Enzyme CYLD/metabolism , HEK293 Cells , Humans , Mice , Mice, Knockout , Protein Stability , Signal Transduction , UbiquitinationABSTRACT
Resveratrol, a major stilbene phytoalexin, is a valuable polyphenol that has been recognized for its benefits to human health. Resveratrol has antioxidant and antitumor effects and promotes longevity. It is used in medicine, health care products, cosmetics, and other industries. Therefore, a sustainable source for resveratrol production is required. This review describes the metabolic engineering of microorganisms, the biotransformation and biosynthesis of endophytes and the oxidation or degradation of resveratrol. We compare various available methods for resveratrol production, and summarize the practical challenges facing the microbial production of resveratrol. The future research direction for resveratrol is also discussed.
