O'Loughlin, T;
Kruppa, AJ;
Ribeiro, ALR;
Edgar, JR;
Ghannam, A;
Smith, AM;
Buss, F;
(2020)
OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion.
Journal of Cell Science
, 133
(12)
, Article jcs239822. 10.1242/jcs.239822.
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Abstract
Optineurin (OPTN) is a multifunctional protein involved in autophagy, secretion as well as NF-κB and IRF3 signalling and OPTN mutations are associated with several human diseases. Here we show that, in response to viral RNA, OPTN translocates to foci in the perinuclear region, where it negatively regulates NF-κB and IRF3 signalling pathways and downstream pro-inflammatory cytokine secretion. These OPTN foci consist of a tight cluster of small membrane vesicles, which are positive for ATG9A. Disease mutations linked to POAG cause aberrant foci formation in the absence of stimuli, which correlates with the ability of OPTN to inhibit signalling. Using proximity labelling proteomics, we identify the LUBAC complex, CYLD and TBK1 as part of the OPTN interactome and show that these proteins are recruited to this OPTN-positive perinuclear compartment. Our work uncovers a crucial role for OPTN in dampening NF-κB and IRF3 signalling through the sequestration of LUBAC and other positive regulators in this viral RNA-induced compartment leading to altered pro-inflammatory cytokine secretion.
Type: | Article |
---|---|
Title: | OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1242/jcs.239822 |
Publisher version: | https://doi.org/10.1242/jcs.239822 |
Language: | English |
Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Keywords: | ATG9A, BioID, Functional proteomics, IFN, LUBAC, Linear ubiquitin, NF-κB, OPTN, TBK1 |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute |
URI: | https://discovery.ucl.ac.uk/id/eprint/10097736 |
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