ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling

• Published in: Nature communications Vol. 14; no. 1; pp. 611 - 22
• Main Authors: Gentili, Matteo, Liu, Bingxu, Papanastasiou, Malvina, Dele-Oni, Deborah, Schwartz, Marc A., Carlson, Rebecca J., Al’Khafaji, Aziz M., Krug, Karsten, Brown, Adam, Doench, John G., Carr, Steven A., Hacohen, Nir
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 14/63; 38/47; 38/91; 631/250/262; 631/80/313/2155; 82/29; 82/58; Degradation; Dendritic cells; Deoxyribonucleic acid; DNA; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; Endosomes; Fibroblasts; Genes; Genetic screening; Hereditary spastic paraplegia; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate; Innate immunity; Interferon; Intracellular; Intracellular signalling; Membrane Proteins - metabolism; Monocytes; multidisciplinary; Nucleotides; Nucleotides, Cyclic - pharmacology; Oligomerization; Paraplegics; Pathogens; Proteomics; Science; Science (multidisciplinary); Signaling; Steady state; Stimulators; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36132-9

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. STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses.