Termination of STING responses is mediated via ESCRT-dependent degradation

Katherine R. Balka, Rajan Venkatraman, Tahnee L. Saunders, Angus Shoppee, Ee Shan Pang, Zoe Magill, Jihane Homman-Ludiye, Cheng Huang, Rachael M. Lane, Harrison M. York, Peck Tan, Ralf B. Schittenhelm, Senthil Arumugam, Benjamin T. Kile, Meredith O'Keeffe, Dominic De Nardo

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

cGAS-STING signalling is induced by detection of foreign or mislocalised host double-stranded (ds)DNA within the cytosol. STING acts as the major signalling hub, where it controls production of type I interferons and inflammatory cytokines. Basally, STING resides on the ER membrane. Following activation STING traffics to the Golgi to initiate downstream signalling and subsequently to endolysosomal compartments for degradation and termination of signalling. While STING is known to be degraded within lysosomes, the mechanisms controlling its delivery remain poorly defined. Here we utilised a proteomics-based approach to assess phosphorylation changes in primary murine macrophages following STING activation. This identified numerous phosphorylation events in proteins involved in intracellular and vesicular transport. We utilised high-temporal microscopy to track STING vesicular transport in live macrophages. We subsequently identified that the endosomal complexes required for transport (ESCRT) pathway detects ubiquitinated STING on vesicles, which facilitates the degradation of STING in murine macrophages. Disruption of ESCRT functionality greatly enhanced STING signalling and cytokine production, thus characterising a mechanism controlling effective termination of STING signalling.

Original languageEnglish
Article numbere112712
Number of pages21
JournalThe EMBO Journal
Volume42
Issue number12
DOIs
Publication statusPublished - 15 Jun 2023

Keywords

  • cGAS-STING
  • ESCRT
  • innate immunity
  • lysosomal degradation
  • vesicular trafficking

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