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• W4319231564 abstract "Abstract Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling." @default.
• W4319231564 created "2023-02-05" @default.
• W4319231564 creator A5007393270 @default.
• W4319231564 creator A5010743762 @default.
• W4319231564 creator A5036255260 @default.
• W4319231564 creator A5038258123 @default.
• W4319231564 creator A5040026307 @default.
• W4319231564 creator A5048859270 @default.
• W4319231564 creator A5051881453 @default.
• W4319231564 creator A5066561471 @default.
• W4319231564 creator A5071412704 @default.
• W4319231564 creator A5074739915 @default.
• W4319231564 creator A5085440029 @default.
• W4319231564 creator A5090428155 @default.
• W4319231564 date "2023-02-04" @default.
• W4319231564 modified "2023-10-17" @default.
• W4319231564 title "ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling" @default.
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