2018
DOI: 10.1080/15548627.2017.1391970
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Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation

Abstract: OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an a… Show more

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Cited by 86 publications
(52 citation statements)
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References 74 publications
(131 reference statements)
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“…Pharmacological inhibition of TBK1 or expression of ALS‐associated TBK1 mutants can reduce the mitophagic efficiency of damaged mitochondria. In conclusion, both OPTN and its upstream protein TBK1 are required for normal mitophagy homeostasis . As shown in these studies, TBK1 phosphorylates OPTN, enhancing its ability to bind to ubiquitinated mitochondria, suggesting that TBK1 may also be one of the potential targets for treating ALS …”
Section: Mitophagy and Neurodegenerative Diseasesmentioning
confidence: 54%
“…Pharmacological inhibition of TBK1 or expression of ALS‐associated TBK1 mutants can reduce the mitophagic efficiency of damaged mitochondria. In conclusion, both OPTN and its upstream protein TBK1 are required for normal mitophagy homeostasis . As shown in these studies, TBK1 phosphorylates OPTN, enhancing its ability to bind to ubiquitinated mitochondria, suggesting that TBK1 may also be one of the potential targets for treating ALS …”
Section: Mitophagy and Neurodegenerative Diseasesmentioning
confidence: 54%
“…The UBAN-containing proteins are NEMO, ABIN1-3 and optineurin. These domains preferentially bind M1-linked ubiquitin chains as well as K63-linked chains (although with lower affinity) but not K48-linked polyubiquitin chains [39][40][41]. The UBAN domains of NEMO (NF-κB essential modulator) and ABIN1 (A20-binding inhibitors of NF-κB) are essential for the regulation of inflammation, tumorigenesis and immunity [42][43][44].…”
Section: Ubiquitination and Ubiquitin-binding Domains: A General Overmentioning
confidence: 99%
“…The H486R mutation in OPTN perturbs the structure of the UBAN domain and causes low-grade inflammation that leads to glaucoma 26 . However, in contrast to other mutants that were shown to have a direct role in interacting with ubiquitin, this residue points inside the coiled-coil, and only reduces the binding affinity 27 . In the third scenario, mutations are occurring in the coiled-coil, however on a residue facing outward.…”
Section: Discussionmentioning
confidence: 60%