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

Matteo Gentili, Bingxu Liu, Malvina Papanastasiou, Deborah Dele-Oni, Marc A. Schwartz, Rebecca J. Carlson, Aziz M. Al’Khafaji, Karsten Krug, Adam Brown, John G. Doench, Steven A. Carr () and Nir Hacohen ()
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Matteo Gentili: Broad Institute of MIT and Harvard
Bingxu Liu: Broad Institute of MIT and Harvard
Malvina Papanastasiou: Broad Institute of MIT and Harvard
Deborah Dele-Oni: Broad Institute of MIT and Harvard
Marc A. Schwartz: Broad Institute of MIT and Harvard
Rebecca J. Carlson: Broad Institute of MIT and Harvard
Aziz M. Al’Khafaji: Broad Institute of MIT and Harvard
Karsten Krug: Broad Institute of MIT and Harvard
Adam Brown: Broad Institute of MIT and Harvard
John G. Doench: Broad Institute of MIT and Harvard
Steven A. Carr: Broad Institute of MIT and Harvard
Nir Hacohen: Broad Institute of MIT and Harvard

Nature Communications, 2023, vol. 14, issue 1, 1-22

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.

Date: 2023
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DOI: 10.1038/s41467-023-36132-9

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