Termination of STING responses is mediated via ESCRT-dependent degradation

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dc.contributor.authorBalka, K.R.
dc.contributor.authorVenkatraman, R.
dc.contributor.authorSaunders, T.L.
dc.contributor.authorShoppee, A.
dc.contributor.authorPang, E.S.
dc.contributor.authorMagill, Z.
dc.contributor.authorHomman-Ludiye, J.
dc.contributor.authorHuang, C.
dc.contributor.authorLane, R.M.
dc.contributor.authorYork, H.M.
dc.contributor.authorTan, P.
dc.contributor.authorSchittenhelm, R.B.
dc.contributor.authorArumugam, S.
dc.contributor.authorKile, B.T.
dc.contributor.authorO'Keeffe, M.
dc.contributor.authorDe Nardo, D.
dc.date.issued2023
dc.descriptionPublished online 4 May 2023
dc.description.abstractcGAS-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.
dc.description.statementofresponsibilityKatherine 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
dc.identifier.citationThe EMBO Journal, 2023; 42(12):e112712-1-e112712-21
dc.identifier.doi10.15252/embj.2022112712
dc.identifier.issn0261-4189
dc.identifier.issn1460-2075
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttps://hdl.handle.net/2440/138495
dc.language.isoen
dc.publisherEMBO
dc.relation.granthttp://purl.org/au-research/grants/arc/DP210103122
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1113577
dc.rights© 2023 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.15252/embj.2022112712
dc.subjectESCRT
dc.subjectcGAS-STING
dc.subjectinnate immunity
dc.subjectlysosomal degradation
dc.subjectvesicular trafficking
dc.titleTermination of STING responses is mediated via ESCRT-dependent degradation
dc.typeJournal article
pubs.publication-statusPublished

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