Posttranslational Modifications, Localization, and Protein Interactions of Optineurin, the Product of a Glaucoma Gene

Ying, Hongyu; Shen, Xiang; Park, Bum-Chan; Yue, Beatrice Y.J.T.

doi:10.1371/journal.pone.0009168

Cited by 56 publications

(92 citation statements)

References 56 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UPP has been shown to be the pathway that degrades in a specific manner short lived proteins. The involvement of UPP is therefore consistent with our finding that the half-life of the endogenous optineurin is ϳ8 h (17). Ubiquitination of the endogenous optineurin also agrees with a previous observation that 35 S-labeled, in vitro-translated optineurin binds to ubiquitin and is ubiquitinated (16).…”

Section: Discussionsupporting

confidence: 93%

“…Tetracycline-regulated (Tet-On) wild type optineurin (OPTN WT )-green fluorescence protein (GFP)-inducible stable RGC5 cell line was established as described previously (17). Tet-On-inducible E50K optineurin (OPTN E50K )-GFP RGC5 cell line was, in addition, created following the same procedures and strategies.…”

Section: Methodsmentioning

confidence: 99%

“…Tet-On-inducible E50K optineurin (OPTN E50K )-GFP RGC5 cell line was, in addition, created following the same procedures and strategies. The only exception was that the OPTN WT -GFP fragment was replaced with OPTN E50K -GFP during the first cloning step (17). The cells were maintained in DMEM complete medium with 10% Tet system certified fetal bovine serum (Clontech), essential and nonessential amino acids, and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

“…Like NF-B essential modulator, optineurin has a polyubiquitin-binding region in the sequence, and it binds Lys-63 linked polyubiquitinated chains (16). Optineurin has in addition been demonstrated to interact with itself to form homo-hexamers (17). It also interacts with proteins, including myosin VI, Rab8, and transferrin receptor.…”

mentioning

confidence: 99%

“…It also interacts with proteins, including myosin VI, Rab8, and transferrin receptor. Super molecular complexes are detected, and granular structures termed foci are formed when optineurin is overexpressed or E50K mutated (17,18).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Processing of Optineurin in Neuronal Cells

Shen

Ying

Qiu

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Optineurin is a gene linked to amyotrophic lateral sclerosis, Paget disease of bone, and glaucoma, a major blinding disease. Mutations such as E50K were identified in glaucoma patients. We investigated herein the involvement of ubiquitin-proteasome pathway (UPP) and autophagy, two major routes for protein clearance, in processing of optineurin in a retinal ganglion cell model line RGC5 and neuronal PC12 cells. It was found that the endogenous optineurin level in neuronal cells was increased by treatment of proteasomal inhibitor but not by autophagic and lysosomal inhibitors. Multiple bands immunoreactive to anti-ubiquitin were seen in the optineurin pulldown, indicating that optineurin was ubiquitinated. In cells overexpressing wild type and E50K optineurin, the level of the proteasome regulatory ␤5 subunit (PSMB5, indicative of proteasome activity) was reduced, whereas that for autophagy marker microtubule-associated protein 1 light chain 3 was enhanced compared with controls. Autophagosome formation was detected by electron microscopy. The foci formed after optineurin transfection were increased upon treatment of an autophagic inhibitor but were decreased by treatment of an inducer, rapamycin. Moreover, the level of optineurin-triggered apoptosis was reduced by rapamycin. This study thus provides compelling evidence that in a normal homeostatic situation, the turnover of endogenous optineurin involves mainly UPP. When optineurin is up-regulated or mutated, the UPP function is compromised, and autophagy comes into play. A decreased PSMB5 level and an induced autophagy were also demonstrated in vivo in retinal ganglion cells of E50K transgenic mice, validating and making relevant the in vitro findings.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Processing of Optineurin in Neuronal Cells

Shen

Ying

Qiu

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

The evolution of selective autophagy as a mechanism of oxidative stress response

Ratliffe,

Kataura,

Otten

et al. 2023

BioEssays

View full text Add to dashboard Cite

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress.

show abstract

Functional analysis of optineurin and some of its disease-associated mutants

2015

View full text Add to dashboard Cite

Optineurin is a multifunctional protein involved in a variety of cellular functions such as protein trafficking by vesicles, autophagy, and signal transduction. Certain mutations in optineurin (gene OPTN) are associated with neurodegenerative diseases like glaucoma and amyotrophic lateral sclerosis (ALS). Optineurin is also seen in pathological structures present in several other neurodegenerative diseases. In glaucoma, loss of vision occurs due to progressive degeneration of retinal ganglion cells, and perhaps loss of photoreceptor cone cells as well. Most of the glaucoma-associated mutations of optineurin are heterozygous missense mutations, whereas the ALS-associated mutations include deletion, truncation, and missense mutations. Optineurin mediates its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more proteins. Disease-causing mutations alter these interactions leading to functional defects in membrane vesicle trafficking, autophagy, signaling, aggregate formation, and other processes. Some of these functional defects, caused by glaucomaassociated mutants of optineurin, led to retinal cell death mediated by apoptosis and therefore may contribute to pathogenesis directly. Other mutations are likely to cause glaucoma by indirect mechanisms involving other cell types. Mechanisms of ALS pathogenesis by optineurin mutations are yet to be investigated in detail; however, some ALSassociated mutants cause defects in signaling, autophagy, and ubiquitin binding, which might contribute to pathogenesis. V C 2015 IUBMB Life, 67(2): [120][121][122][123][124][125][126][127][128] 2015

show abstract

Posttranslational Modifications, Localization, and Protein Interactions of Optineurin, the Product of a Glaucoma Gene

Cited by 56 publications

References 56 publications

Processing of Optineurin in Neuronal Cells

Processing of Optineurin in Neuronal Cells

The evolution of selective autophagy as a mechanism of oxidative stress response

Functional analysis of optineurin and some of its disease-associated mutants

Contact Info

Product

Resources

About