RT Journal Article
SR Electronic
T1 OPTN translocates to an ATG9A-positive compartment to regulate innate immune signalling and cytokine secretion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 744672
DO 10.1101/744672
A1 Thomas O’Loughlin
A1 Antonina J Kruppa
A1 Andre LR Ribeiro
A1 James R Edgar
A1 Abdulaziz Ghannam
A1 Andrew M Smith
A1 Folma Buss
YR 2019
UL http://biorxiv.org/content/early/2019/08/22/744672.abstract
AB Optineurin (OPTN) is a multifunctional protein involved in autophagy, secretion as well as NF-κB and IRF3 signalling and mutations are associated with several human diseases including primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), Paget’s disease of bone (PDB) and Crohn’s disease (CD). 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 marker proteins of the trans-Golgi network/recycling compartment – most notably ATG9A. Disease mutations linked to POAG cause aberrant formation of this compartment in the absence of stimuli, which correlates with the ability of OPTN to inhibit signalling. Using proximity labelling proteomics (BioID), we identify the linear ubiquitin assembly complex (LUBAC), CYLD and TBK1 as part of the OPTN interactome and show that these proteins, along with NEMO, are recruited to this OPTN-positive perinuclear compartment. Together, we propose OPTN might be responsible for dampening the NF-κB and IRF3 signalling responses through the sequestration of LUBAC and other positive regulators of these pathways in this dsRNA-induced compartment leading to altered pro-inflammatory cytokine secretion.Summary Disease associated OPTN mutations impact on the formation of the perinuclear compartment and result in hypo- or hyper-activation of the immune response, which could drive the development of human diseases such as POAG, ALS and also Paget’s disease of bone.