Inducible turnover of optineurin regulates T cell activation

Montecalvo, Angela; Watkins, Simon C.; Kane, Lawrence P.

doi:10.1016/j.molimm.2017.01.027

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Optineurin directly competes with NEMO for the binding to ubiquitylated RIP ( 33 ) and recruits CYLD, which deubiquitinates RIP to inhibit NF-κB activation ( 40 ). Recently, it was shown that activation of T-cell receptor signalling triggers the degradation of optineurin to overcome optineurin’s negative regulation of NF-κB signalling, which acts to suppress T-cell activation ( 59 ). Interestingly, NF-κB upregulates OPTN expression ( 60 ), suggesting a negative feedback loop exists to ensure proper regulation of NF-κB signalling.…”

Section: Role Of Optineurin In Signalling and Intracellular Traffickimentioning

confidence: 99%

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Ryan

Tumbarello

2018

Front. Immunol.

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Optineurin is a multifunctional adaptor protein intimately involved in various vesicular trafficking pathways. Through interactions with an array of proteins, such as myosin VI, huntingtin, Rab8, and Tank-binding kinase 1, as well as via its oligomerisation, optineurin has the ability to act as an adaptor, scaffold, or signal regulator to coordinate many cellular processes associated with the trafficking of membrane-delivered cargo. Due to its diverse interactions and its distinct functions, optineurin is an essential component in a number of homeostatic pathways, such as protein trafficking and organelle maintenance. Through the binding of polyubiquitinated cargoes via its ubiquitin-binding domain, optineurin also serves as a selective autophagic receptor for the removal of a wide range of substrates. Alternatively, it can act in an ubiquitin-independent manner to mediate the clearance of protein aggregates. Regarding its disease associations, mutations in the optineurin gene are associated with glaucoma and have more recently been found to correlate with Paget’s disease of bone and amyotrophic lateral sclerosis (ALS). Indeed, ALS-associated mutations in optineurin result in defects in neuronal vesicular localisation, autophagosome–lysosome fusion, and secretory pathway function. More recent molecular and functional analysis has shown that it also plays a role in mitophagy, thus linking it to a number of other neurodegenerative conditions, such as Parkinson’s. Here, we review the role of optineurin in intracellular membrane trafficking, with a focus on autophagy, and describe how upstream signalling cascades are critical to its regulation. Current data and contradicting reports would suggest that optineurin is an important and selective autophagy receptor under specific conditions, whereby interplay, synergy, and functional redundancy with other receptors occurs. We will also discuss how dysfunction in optineurin-mediated pathways may lead to perturbation of critical cellular processes, which can drive the pathologies of number of diseases. Therefore, further understanding of optineurin function, its target specificity, and its mechanism of action will be critical in fully delineating its role in human disease.

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Section: Role Of Optineurin In Signalling and Intracellular Traffickimentioning

confidence: 99%

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Ryan

Tumbarello

2018

Front. Immunol.

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“…The OPTN gene (optineurin; MIM#602432) is localized on chromosome 10 at 10p13, encoding the protein optineurin which regulates vesicular transport [170] and NF-KB signaling [171]. Wong and Holzbaur [172] found, using live-cell microscopy, that optineurin is recruited to impaired mitochondria after PARKIN recruitment and stabilised via ubiquitin binding to ABIN and NEMO (UBAN) domain and eventually recruits LC3 via its LIR domain, leading to autophagosome formation.…”

Section: Optnmentioning

confidence: 99%

The Role of Mitophagy in Glaucomatous Neurodegeneration

Stavropoulos,

Grewal,

Petriti

et al. 2023

Cells

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This review aims to provide a better understanding of the emerging role of mitophagy in glaucomatous neurodegeneration, which is the primary cause of irreversible blindness worldwide. Increasing evidence from genetic and other experimental studies suggests that mitophagy-related genes are implicated in the pathogenesis of glaucoma in various populations. The association between polymorphisms in these genes and increased risk of glaucoma is presented. Reduction in intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, while clinical trials highlight the inadequacy of IOP-lowering therapeutic approaches to prevent sight loss in many glaucoma patients. Mitochondrial dysfunction is thought to increase the susceptibility of retinal ganglion cells (RGCs) to other risk factors and is implicated in glaucomatous degeneration. Mitophagy holds a vital role in mitochondrial quality control processes, and the current review explores the mitophagy-related pathways which may be linked to glaucoma and their therapeutic potential.

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“…A mutant version of OPTN that fails to recruit CYLD to inhibit NF-κB activation in response to TNF is also unable to inhibit IRAK-1-induced NF-κB signaling ( 12 , 13 ). Finally, OPTN was recently shown to suppress T cell receptor-induced NF-κB activation and TNF production, in a manner dependent on ubiquitin-binding ( 14 ).…”

Section: Optn and Nuclear Factor-κb (Nf-κb) Signalingmentioning

confidence: 99%

Optineurin Functions for Optimal Immunity

Slowicka

Loo

2018

Front. Immunol.

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Optineurin (OPTN) was identified 20 years ago in a yeast-two-hybrid screen with a viral protein known to inhibit the cytolytic effects of tumor necrosis factor. Since then, OPTN has been identified as a ubiquitin-binding protein involved in many signaling pathways and cellular processes, and mutations in the OPTN gene have been associated with glaucoma, Paget’s disease of bone and neurodegenerative pathologies. Its role in autophagy, however, has attracted most attention in recent years and may explain (some of) the mechanisms behind the disease-associated mutations of OPTN. In this brief review, we focus on the role of OPTN in inflammation and immunity and describe how this may translate to its involvement in human disease.

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Inducible turnover of optineurin regulates T cell activation

Cited by 9 publications

References 39 publications

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

The Role of Mitophagy in Glaucomatous Neurodegeneration

Optineurin Functions for Optimal Immunity

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