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

Feb 06, 2023

Experts: 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,Nir Hacohen

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.
© 2023. The Author(s).

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ABOUT THE EXPERTS

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,Nir Hacohen

Matteo Gentili

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Bingxu Liu

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.

Malvina Papanastasiou

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Deborah Dele-Oni

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Marc A Schwartz

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

Rebecca J Carlson

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Massachusetts Institute of Technology, Department of Health Sciences and Technology, Cambridge, MA, USA.

Aziz M Al’Khafaji

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Karsten Krug

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Adam Brown

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

John G Doench

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Steven A Carr

Broad Institute of MIT and Harvard, Cambridge, MA, USA. scarr@broad.mit.edu.

Nir Hacohen

Broad Institute of MIT and Harvard, Cambridge, MA, USA. nhacohen@mgh.harvard.edu.

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. nhacohen@mgh.harvard.edu.

Center for Cancer Research, Massachusetts General Hospital, Boston, MA, 02114, USA. nhacohen@mgh.harvard.edu.