1. Termination of STING responses is mediated via ESCRT‐dependent degradation.
- Author
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Balka, Katherine R, Venkatraman, Rajan, Saunders, Tahnee L, Shoppee, Angus, Pang, Ee Shan, Magill, Zoe, Homman‐Ludiye, Jihane, Huang, Cheng, Lane, Rachael M, York, Harrison M, Tan, Peck, Schittenhelm, Ralf B, Arumugam, Senthil, Kile, Benjamin T, O'Keeffe, Meredith, and De Nardo, Dominic
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TYPE I interferons , *VENOM , *PRODUCTION control - 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. Synopsis: Effective termination of STING signalling is crucial to prevent unwarranted inflammation. Utilising biochemical and microscopy approaches, here we identify that the ESCRT pathway facilitates STING degradation and shuts off immune signalling. STING activation induces phosphorylation changes in a large number of intracellular trafficking proteins.Ubiquitination of STING is essential for its degradation.The ESCRT pathway mediates the termination of STING responses. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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