The Role of Optineurin in Immunity and Immune-Mediated Diseases

Editorial

11 December 2019

Editorial: The Role of Optineurin in Immunity and Immune-Mediated Diseases

Andrew M. Smith

Folma Buss

and

Ivana Munitic

2,828 views

0 citations

Editors

Andrew Mark Smith

University College London

Ivana Munitic

University of Rijeka

Folma Buss

University of Cambridge

Impact

Review

19 June 2018

Role of Optineurin in the Mitochondrial Dysfunction: Potential Implications in Neurodegenerative Diseases and Cancer

Robert Weil

, 2 more and

Pierre Génin

Optineurin (Optn) is a 577 aa protein encoded by the Optn gene. Mutations of Optn are associated with normal tension glaucoma and amyotrophic lateral sclerosis, and its gene has also been linked to the development of Paget’s disease of bone and Crohn’s disease. Optn is involved in diverse cellular functions, including NF-κB regulation, membrane trafficking, exocytosis, vesicle transport, reorganization of actin and microtubules, cell cycle control, and autophagy. Besides its role in xenophagy and autophagy of aggregates, Optn has been identified as a primary autophagy receptor, among the five adaptors that translocate to mitochondria during mitophagy. Mitophagy is a selective macroautophagy process during which irreparable mitochondria are degraded, preventing accumulation of defective mitochondria and limiting the release of reactive oxygen species and proapoptotic factors. Mitochondrial quality control via mitophagy is central to the health of cells. One of the important surveillance pathways of mitochondrial health is the recently defined signal transduction pathway involving the mitochondrial PTEN-induced putative kinase 1 (PINK1) protein and the cytosolic RING-between-RING ubiquitin ligase Parkin. Both of these proteins, when mutated, have been identified in certain forms of Parkinson’s disease. By targeting ubiquitinated mitochondria to autophagosomes through its association with autophagy related proteins, Optn is responsible for a critical step in mitophagy. This review reports recent discoveries on the role of Optn in mitophagy and provides insight into its link with neurodegenerative diseases. We will also discuss the involvement of Optn in other pathologies in which mitophagy dysfunctions are involved including cancer.

21,800 views

68 citations

Original Research

14 November 2018

ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death

Zhengzhao Liu

, 10 more and

Ronggui Hu

9,027 views

38 citations

Optineurin mediates vesicular trafficking, receptor recycling and autophagy. (1) Optineurin controls Rab8 and myosin localization at the Golgi apparatus. Depletion of optineurin relocates the optineurin–Rab8–myosinVI complex from the Golgi. (2) Depletion of optineurin or overexpression of wild-type, ALS, or glaucoma mutant optineurin, results in Golgi fragmentation. (3) During vesicular trafficking, secretory vesicles travel from the Golgi to the plasma membrane where they fuse and undergo exocytosis. Depletion of optineurin abolishes the fusion of vesicles with the plasma membrane. (4) Transferrin receptor is recycled to the surface after transferrin uptake. E50K glaucoma mutant optineurin inhibits transferrin uptake, whilst depletion and overexpression of optineurin abolishes the recycling of transferrin receptor. M98K glaucoma mutant induces autophagic degradation of transferrin receptors by targeting them to autophagosomes. (5) Optineurin disrupts autophagy at several stages. The formation of the phagophore and autophagosome is inhibited by depletion of optineurin, as well as overexpression of ALS mutant optineurin, by inhibiting ATG5/ATG12/ATG6L1 complex formation. Optineurin links the ubiquitinated cargo to LC3, together facilitating autophagosomal engulfment of the cargo. Degradation of cargo, such as mitochondria and protein aggregates, is inhibited by both ALS and glaucoma mutant optineurin. Imbalance of optineurin expression, such as its overexpression or depletion, also interferes with autophagy, decreasing the clearance of cargo. ALS-associated mutant optineurin further blocks the fusion of the autophagosome to the lysosome, further inhibiting autophagy flux. Abbreviations: OPTN−: optineurin depletion, OPTN+: optineurin overexpression, OPTN ALS: ALS mutant optineurin, OPTN glaucoma: glaucoma mutant optineurin, Tf: transferrin, TfR: transferrin receptor, ER: endoplasmic reticulum.

Review

23 May 2018

Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma

Reka P. Toth

and

Julie D. Atkin

Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and glaucoma, affect millions of people worldwide. ALS is caused by the loss of motor neurons in the spinal cord, brainstem, and brain, and genetic mutations are responsible for 10% of all ALS cases. Glaucoma is characterized by the loss of retinal ganglion cells and is the most common cause of irreversible blindness. Interestingly, mutations in OPTN, encoding optineurin, are associated with both ALS and glaucoma. Optineurin is a highly abundant protein involved in a wide range of cellular processes, including the inflammatory response, autophagy, Golgi maintenance, and vesicular transport. In this review, we summarize the role of optineurin in cellular mechanisms implicated in neurodegenerative disorders, including neuroinflammation, autophagy, and vesicular trafficking, focusing in particular on the consequences of expression of mutations associated with ALS and glaucoma. This review, therefore showcases the impact of optineurin dysfunction in ALS and glaucoma.

14,518 views

92 citations

Optineurin (OPTN) acts as a molecular switch that maintains a balance between transferrin receptor (TFRC) recycling and autophagy in retinal cells. M98K mutation in OPTN alters this balance leading to enhanced autophagy that in turn results in reduced recycling of TFRC. Enhanced phosphorylation of M98K-OPTN by TBK1 at S177 plays a crucial role in autophagy-dependent degradation of TFRC leading to cell death.

Review

06 June 2018

Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin

Ghanshyam Swarup

and

Zuberwasim Sayyad

7,826 views

59 citations

Review

15 May 2018

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

Thomas A. Ryan

and

David A. Tumbarello

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.

12,389 views

101 citations