A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

Sirohi, Kapil; Kumari, Asha; Radha, Vegesna; Swarup, Ghanshyam

doi:10.1371/journal.pone.0138289

Cited by 40 publications

(45 citation statements)

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“…Another study linked loss-of-function TBK1 mutations to both ALS and FTD (21). Finally, mutations in both TBK1 and OPTN are causal for both ALS and glaucoma (20,31). In this study, we observed that the ALS-associated mutants TBK1-E696K, OPTN-E478G, and OPTN-Q398X all interfere with efficient autophagic engulfment of damaged mitochondria.…”

Section: Discussionmentioning

confidence: 51%

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

Moore

Holzbaur

2016

Proc. Natl. Acad. Sci. U.S.A.

280

266

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Mitochondria play an essential role in maintaining cellular homeostasis. The removal of damaged or depolarized mitochondria occurs via mitophagy, in which damaged mitochondria are targeted for degradation via ubiquitination induced by PTEN-induced putative kinase 1 (PINK1) and Parkin. Mitophagy receptors, including optineurin (OPTN), nuclear dot 52 kDa protein (NDP52), and Tax1-binding protein 1 (TAX1BP1), are recruited to mitochondria via ubiquitin binding and mediate autophagic engulfment through their association with microtubule-associated protein light chain 3 (LC3). Here, we use livecell imaging to demonstrate that OPTN, NDP52, and TAX1BP1 are recruited to mitochondria with similar kinetics following either mitochondrial depolarization or localized generation of reactive oxygen species, leading to sequestration by the autophagosome within ∼45 min after insult. Despite this corecruitment, we find that depletion of OPTN, but not NDP52, significantly slows the efficiency of sequestration. OPTN is phosphorylated by the kinase TANK-binding kinase 1 (TBK1) at serine 177; we find that TBK1 is corecruited with OPTN to depolarized mitochondria. Inhibition or depletion of TBK1, or expression of amyotrophic lateral sclerosis (ALS)-associated OPTN or TBK1 mutant blocks efficient autophagosome formation. Together, these results indicate that although there is some functional redundancy among mitophagy receptors, efficient sequestration of damaged mitochondria in response to mitochondrial stress requires both TBK1 and OPTN. Notably, ALSlinked mutations in OPTN and TBK1 can interfere with mitophagy, suggesting that inefficient turnover of damaged mitochondria may represent a key pathophysiological mechanism contributing to neurodegenerative disease.itochondria form interconnected networks that continuously remodel in response to shifting cellular needs (1). These dynamic networks serve as hubs for diverse cellular functions, including aerobic metabolism, calcium homeostasis (2), and redox signaling (3). Several key mitochondrial functions rely on the potential across the mitochondrial inner membrane. Loss of membrane potential is associated with mitochondrial fragmentation and impaired trafficking (4), and can potentially activate cell death pathways (5). To safeguard against these deleterious outcomes, eukaryotic cells have developed quality control mechanisms to monitor the membrane potential of resident mitochondria and selectively eliminate depolarized organelles through mitophagy.In mitophagy, damaged mitochondria are recognized and then sequestered by a double-membrane autophagosome, leading to selective degradation. Regulation of this process involves the ubiquitin kinase PTEN-induced putative kinase 1 (PINK1) (6) and the E3-ubiquitin ligase Parkin (7). Specifically, PINK1 accumulates on the surface of depolarized mitochondria, where it phosphorylates ubiquitin on local outer membrane proteins, resulting in the recruitment of Parkin (7-11). Parkin, in turn, modifies additional mitochondrial outer membrane proteins...

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Section: Discussionmentioning

confidence: 51%

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

Moore

Holzbaur

2016

Proc. Natl. Acad. Sci. U.S.A.

280

266

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“…In a recent work, our laboratory reported the dysregulation of autophagy with aging and in TM cells isolated from glaucoma cadaver eyes 17 . A connection between autophagy and neurodegeneration in glaucoma is strongly supported from the discovery that the optineurin and TANK Binding Kinase (TBK1), normal tension glaucoma (NTG)-associated genes, are essential players in the autophagic degradation of damaged mitochondria, a process known as mitophagy 20,21 . Activation of autophagy in RGCs in response to injury (ON transection) or elevated IOP (acute or chronic) has been reported in different induced models of experimental glaucoma 22–28 .…”

Section: Introductionmentioning

confidence: 99%

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

et al. 2018

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Glaucoma is a progressive optic neuropathy characterized by axonal degeneration and retinal ganglion cells loss. Several factors have been postulated to play a role in glaucoma, elevated intraocular pressure (IOP) being the best well-known causative factor. The mechanisms leading to ocular hypertension and glaucoma are still not fully understood. An increasing number of evidence indicates a role of autophagy in the pathophysiological process of ocular hypertension and glaucoma. However, while all of the studies agree that autophagy is induced in RGCs in response to injury, autophagy was found to either protect or promote cell death depending on the experimental model used. In order to gain more insight into both, the role of autophagy in the pathogenesis of glaucoma and the effect of chronic IOP elevation in the autophagy pathway, we have investigated here for the first time autophagy in the iridocorneal angle region, retinal ganglion cell bodies, and ON axons in the spontaneous ocular hypertensive DBA/2J mouse glaucoma model and in the transgenic DBA/2J::GFP-LC3 mice, generated in our laboratory. Our results indicate decreased autophagic flux in the outflow pathway cells in the DBA/2J mice, characterized by increased levels of LC3-II and p62 together with a decrease in the lysosomal marker LAMP1, evaluated by western blot and immunofluorescence. Elevated presence of autophagic vacuoles in the DBA/2J and, in particular, in the DBA/2J::GFP-LC3 mice was also observed. Expression of the GFP-LC3 transgene was associated to higher cumulative IOP in the DBA/2J background. In addition to higher elevation in IOP, DBA/2J::GFP-LC3 were characterized by further RGCs and exacerbated axonal degeneration compared to DBA/2J. This was accompanied by the notable high presence of autophagic figures within degenerating axons. These results strongly suggest overactivation of autophagy as a potential cellular mechanism leading to ON degeneration in the chronic hypertensive DBA/2J mice.

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“…OPTN point mutations have been linked to glaucoma or ALS and evidence implicates impaired autophagy and compromised mitochondrial integrity as key pathogenic mechanisms (Chalasani et al, 2014;Sirohi et al, 2015;Wong and Holzbaur, 2014). Autophagy disruptions and mitochondrial dysfunction occur in PD and are likely key pathogenic events in the earliest disease stages (Parker et al, 1989;Tan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Further, metaanalysis of genome-wide association studies shows that single nucleotide polymorphisms in OPTN may increase PD risk. Specifically, the M98K mutation, which likely affects OPTNmediated autophagy, causes glaucoma and was identified as a PD risk modulator (Lill et al, 2012;Sirohi et al, 2015). Thus, mechanistic and genetic data provide a strong rationale for investigation in PD.…”

Section: Discussionmentioning

confidence: 99%

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

Wise

Cannon

2016

Toxicol. Sci.

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Parkinson's disease (PD) is a progressive neurodegenerative disease that affects $5 million people around the world. PD etiopathogenesis is poorly understood and curative or disease modifying treatments are not available. Mechanistic studies have identified numerous pathogenic pathways that overlap with many other neurodegenerative diseases. Mutations in the protein optineurin (OPTN) have recently been identified as causative factors for glaucoma and amyotrophic lateral sclerosis. OPTN has multiple recognized roles in neurons, notably in mediating autophagic flux, which has been found to be disrupted in most neurodegenerative diseases. OPTN þ aggregates have preliminarily been identified in cytoplasmic inclusions in numerous neurodegenerative diseases, however, whether OPTN has a role in PD pathogenesis has yet to be tested. Thus, we chose to test the hypothesis that OPTN expression and localization would be modulated in pre-clinical PD models. To test our hypothesis, we characterized midbrain OPTN expression in normal rats and in a rat rotenone PD model. For the first time, we show that OPTN is enriched in dopamine neurons in the midbrain, and its expression is modulated by rotenone treatment in vivo. Here, animals were sampled at time-points both prior to overt neurodegeneration and after severe behavioral deficits, where a lesion to the nigrostriatal dopamine system is present. The effect and magnitude of OPTN expression changes are dependent on duration of treatment. Furthermore, OPTN colocalizes with LC3 (autophagic vesicle marker) and alpha-synuclein positive puncta in rotenone-treated animals, potentially indicating an important role in autophagy and PD pathogenesis.

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A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

Cited by 40 publications

References 72 publications

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

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