E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis

Systemic lupus erythematosus(SLE)is a systemic autoimmune disease,and the pathogenesis of SLE has not been fully elucidated.The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor that can promote the ubiquitination and subsequent degradation of various oncoproteins;however,the potential role of FBXW7 in autoimmune diseases is unclear.In the present study,we identified that FBXW7 is a crucial exacerbating factor for SLE development and progression in a mouse model induced by 2,6,10,14-tetramethylpentadecane(TMPD).Myeloid cell-specific FBXW7-deficient(Lysm+FBXW7f/f)C57BL/6 mice showed decreased immune complex accumulation,glomerulonephritis,glomerular mesangial cell proliferation,and basemembrane thickness in the kidney.Lysm+FBXW7f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells.In Lysm+FBXW7f/f mice,we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chi inflammatory monocytes were recruited to the peritoneal cavity.Consistently,diffuse pulmonary hemorrhage(DPH)was also decreased in Lysm+FBXW7f/f mice.Mechanistically,we clarified that FBXW7 promoted TMPD-induced cell apoptosis by catalyzing MCL1 degradation through K48-linked ubiquitination.Our work revealed that FBXW7 expression in myeloid cells played a crucial role in TMPD-induced SLE progression in mice,which may provide novel ideas and theoretical support for understanding the pathogenesis of SLE.

MicroRNA-33/33^(*) inhibit the activation of MAVS through AMPK in antiviral innate immunity

Innate immunity plays a prominent role in the host defense against pathogens and must be precisely regulated.As vital orchestrators in cholesterol homeostasis,microRNA-33/33*have been widely investigated in cellular metabolism.However,their role in antiviral innate immunity is largely unknown.Here,we report that VSV stimulation decreased the expression of miR-33/33*through an IFNAR-dependent manner in macrophages.Overexpression of miR-33/33*resulted in impaired RIG-I signaling,enhancing viral load and lethality whereas attenuating type I interferon production both in vitro and in vivo.In addition,miR-33/33*specifically prevented the mitochondrial adaptor mitochondrial antiviral-signaling protein(MAVS)from forming activated aggregates by targeting adenosine monophosphate activated protein kinase(AMPK),subsequently impeding the mitophagy-mediated elimination of damaged mitochondria and disturbing mitochondrial homeostasis which is indispensable for efficient MAVS activation.Our findings establish miR-33/33*as negative modulators of the RNA virus-triggered innate immune response and identify a previously unknown regulatory mechanism linking mitochondrial homeostasis with antiviral signaling pathways.