Interaction between optineurin and the b<scp>ZIP</scp> transcription factor NRL

Wang, Chunxia; Hosono, Katsuhiro; Ohtsubo, Masafumi; Ohishi, Kentaro; Gao, Jie; Nakanishi, Nobuo; Hikoya, Akiko; Sato, M.; Hotta, Yoshihiro; Minoshima, Shinsei

doi:10.1002/cbin.10174

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…5b ). Surprisingly, we also observed a minor degree of colocalization of OPTN and NRF2 in the nucleus, suggesting that a small amount of nuclear OPTN could bind to NRF2, which is consistent with previous reports that OPTN was detected in the nucleus under either stress or overexpression conditions 42 , 49 . However, our results indicated that the amount of OPTN- and NRF2-binding proteins in the nucleus was much lower than that in the cytoplasm, indicating that the cytoplasmic interaction between OPTN and NRF2 is the likely dominant binding pattern between OPTN and NRF2 in preosteoclasts during osteoclastogenesis.…”

Section: Resultssupporting

confidence: 93%

“…Our discovery of a direct interaction between OPTN and NRF2 was based on reports that both OPTN and NRF2 contain a basic domain leucine zipper (bZIP) domain, a key feature of transcription factors that are capable of mediating dimerization, transcriptional regulation, and DNA binding 53 . This finding is consistent with a recent study that showed that OPTN can interact with the bZIP transcription factor neural retina leucine zipper (NRL) in the nucleus of HeLaS3 cells 42 . Immunoprecipitation demonstrated a direct OPTN-NRF2 interaction, and we also found through immunofluorescence staining of endogenous OPTN and NRF2 that they were colocalized primarily in the perinuclear cytoplasm in preosteoclasts during osteoclastogenesis.…”

Section: Discussionsupporting

confidence: 93%

“…NRF2 has a basic-region leucine zipper (bZIP) domain 39 that allows it to heterodimerize with other proteins, regulates its stability, and modulates transcriptional activity 40 , 41 . Interestingly, OPTN also contains a bZIP domain 42 , identifying it as a potential NRF2 binding partner that might contribute to the regulation of ROS levels and osteoclastogenesis 43 . However, the direct Nrf2 and OPTN interaction as a ROS homeostatic mechanism has not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response

Xue

Chang

et al. 2021

Exp Mol Med

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Abnormally increased resorption contributes to bone degenerative diseases such as Paget’s disease of bone (PDB) through unclear mechanisms. Recently, the optineurin (OPTN) gene has been implicated in PDB, and global OPTN knockout mice (Optn−/−) were shown to exhibit increased formation of osteoclasts (osteoclastogenesis). Growing evidence, including our own, has demonstrated that intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can act as signaling molecules to promote osteoclastogenesis. Here, we report that OPTN interacts with nuclear factor erythroid-derived factor 2-related factor 2 (NRF2), the master regulator of the antioxidant response, defining a pathway through which RANKL-induced ROS could be regulated for osteoclastogenesis. In this study, monocytes from Optn−/− and wild-type (Optn+/+) mice were utilized to differentiate into osteoclasts, and both qRT-PCR and tartrate-resistant acid phosphatase (TRAP) staining showed that the Optn−/− monocytes exhibited enhanced osteoclastogenesis compared to the Optn+/+ cells. CellROX® staining, qRT-PCR, and Western blotting indicated that OPTN deficiency reduced the basal expression of Nrf2, inhibited the expression of NRF2-responsive antioxidants, and increased basal and RANKL-induced intracellular ROS levels, leading to enhanced osteoclastogenesis. Coimmunoprecipitation (co-IP) showed direct interaction, and immunofluorescence staining showed perinuclear colocalization of the OPTN-NRF2 granular structures during differentiation. Finally, curcumin and the other NRF2 activators attenuated the hyperactive osteoclastogenesis induced by OPTN deficiency. Collectively, our findings reveal a novel OPTN-mediated mechanism for regulating the NRF2-mediated antioxidant response in osteoclasts and extend the therapeutic potential of OPTN in the aging process resulting from ROS-triggered oxidative stress, which is associated with PDB and many other degenerative diseases.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response

Xue

Chang

et al. 2021

Exp Mol Med

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“…The role of optineurin as an adaptor across many cellular processes is made possible by its ability to interact with a large number of proteins (Figure 1 A). Through its functional interactions with TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1) ( 20 – 22 ), LC3 ( 22 , 23 ), myosin VI ( 24 – 28 ), tax1 binding protein 1 (TAX1BP1) ( 29 ), Rab8 ( 25 , 30 ), huntingtin (Htt) ( 30 , 31 ), transferrin receptor ( 32 ), adenovirus E3-14.7K ( 1 ), receptor-interacting protein (RIP) ( 33 ), the bZIP transcription factor neural retina leucine zipper ( 34 ), myosin phosphatase targeting subunit 1 ( 35 ), transcription factor IIA ( 36 ), SOD1 ( 37 ), caspase 8 ( 38 ), HACE1 ( 39 ), CYLD ( 40 ), or metabotropic glutamate receptor 1 and 5 ( 41 ), optineurin can regulate a multitude of pathways. In addition to these interactions, optineurin can also oligomerise to form homo-hexameric structures ( 42 ), which are likely to have distinct roles from the monomeric form.…”

Section: Optineurin Protein Domain Structure and Interacting Partnersmentioning

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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“…We found that full length OPTN was significantly conserved among these different species, similar to the nearest paralogue, IKBKG ( Table S1 ). We also found that the protein sequences for the binding sites for TBK1 [98] , MYO6 [51] , CYLD [50] , UB [49] and NRL [99] were all significantly conserved between human and zebrafish orthologues (visualized in Fig. 1 , analyzed in Table S1 ).…”

Section: Resultsmentioning

confidence: 71%

Loss of Optineurin In Vivo Results in Elevated Cell Death and Alters Axonal Trafficking Dynamics

Paulus

Link

2014

PLoS ONE

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Mutations in Optineurin have been associated with ALS, glaucoma, and Paget’s disease of bone in humans, but little is known about how these mutations contribute to disease. Most of the cellular consequences of Optineurin loss have come from in vitro studies, and it remains unclear whether these same defects would be seen in vivo. To answer this question, we assessed the cellular consequences of Optineurin loss in zebrafish embryos to determine if they showed the same defects as have been described in the in vitro studies. We found that loss of Optineurin resulted in increased cell death, as well as subtle cell morphology, cell migration and vesicle trafficking defects. However, unlike experiments on cells in culture, we found no indication that the Golgi apparatus was disrupted or that NF-κB target genes were upregulated. Therefore, we conclude that in vivo loss of Optineurin shows some, but not all, of the defects seen in in vitro work.

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Interaction between optineurin and the bZIP transcription factor NRL

Cited by 6 publications

References 26 publications

Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response

Deficiency of optineurin enhances osteoclast differentiation by attenuating the NRF2-mediated antioxidant response

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

Loss of Optineurin In Vivo Results in Elevated Cell Death and Alters Axonal Trafficking Dynamics

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