The Mechanisms Of USP19 Regulating Innate Immune Response And Inflammatory Response

Innate immune and inflammatory responses are very important for host defense against pathogenic microorganisms infection.The efficient innate immune responses and inflammatory responses are beneficial to host self-protection,which can help the host to suppress microbial replication,clean up the infected cells,as well as facilitate the adaptive immunity.However,excessive immune responses would do harmful damage to host or even lead to the occurrence of autoimmune diseases.Therefore,our laboratory research focus on the mechanisms by which immune and inflammatory responses are effectively initiated and terminated,which may provide new therapeutic ideas for curing autoimmune diseases.TIR domain-containing adaptor inducing interferon-?(TRIF)is an essential adaptor protein required for Toll like receptor(TLR)3-and 4-mediated innate immune responses.In this study,we identified USP19 as a negative regulator of TLR3/4-mediated signaling.USP19-deficiency increased poly(I:C)-and LPS-induced production of type I interferons(IFNs)and proinflammatory cytokines in cells and mice.Usp19^-/-mice exhibited more serious inflammation after poly(I:C)or LPS treatment,and were more susceptible to inflammatory death following Salmonella typhimurium infection.USP19 interacted with TRIF and catalyzed the removal of its K27-linked polyubiquitination,resulting in impairment of the recruitment of TRIF to TLR3 and TLR4.We further found that the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzed K27-linked polyubiquitination of TRIF,and deficiency of this complex inhibited TLR3/4-mediated innate immune signaling.Our findings reveal that K27-linked polyubiquitination and deubiquitination of the central adaptor TRIF is a critical regulatory mechanism of TLR3/4-mediated innate immune response.In another study,we identified ubiquitin-specific protease19(USP19)as a negative regulator of tumor necrosis factor?(TNF?)-and interleukin-1?(IL-1?)-triggered NF-?B activation by mediating the deubiquitination of TGF?-activated kinase 1(TAK1).Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF?-and IL-1?-triggered NF-?B activation and transcription of downstream genes,while USP19-deficiency had the opposite effects.Usp19^-/-mice produced higher levels of inflammatory cytokines and were more susceptible to TNF?-and IL-1?-triggered septicemia death comparing to their wild-type littermates.Mechanistically,USP19interacted with TAK1 in a TNF?-or IL-1?-dependent manner,and specifically deconjugated K63-and K27-linked polyubiquitin chains from TAK1,leading to impairment of TAK1 activity and disruption of the TAK1-TAB2/3 complex.Our findings provide new insights to the complicated molecular mechanisms of attenuation of inflammatory response.To sum up,we identified two different mechanisms by which USP19 negatively regulates TLR3/4-mediated innate immune responses and TNF?-and IL-1?-triggered inflammatory responses,respectively.Our studies reveal detailed mechanisms by which the host keeps the homeostasis of the innate immune system in-check to avoid excessive and harmful immune responses,which provide potential targets for the treatment of immune diseases and the development of related drugs.