The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIP_L to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

TNF receptor 2 (TNFR2) exerts diverse roles in the pathogenesis of inflammatory and autoimmune diseases. Here, we report that TNFR2 but not TNFR1 forms a heteromer with interleukin-17 receptor D (IL-17RD), also named Sef, to activate NF-κB signaling. TNFR2 associates with IL-17RD, leading to mutual receptor aggregation and TRAF2 recruitment, which further activate the downstream cascade of NF-κB signaling. Depletion of IL-17RD impaired TNFR2-mediated activation of NF-κB signaling. Importantly, IL-17RD was markedly increased in renal tubular epithelial cells in nephritis rats, and a strong interaction of TNFR2 and IL-17RD was observed in the renal epithelia. The IL-17RD·TNFR2 complex in activation of NF-κB may explain the role of TNFR2 in inflammatory diseases including nephritis.

Amyloid-β (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Aβ aggregation has long

Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR–sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.