5eof

Structural highlights

Disease

[OPTN_HUMAN] Amyotrophic lateral sclerosis;Congenital glaucoma. Primary open angle glaucoma 1E (GLC1E) [MIM:137760]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. The disease is asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. Note=The disease is caused by mutations affecting the gene represented in this entry.^{[1] [2] [3] [4] [5] [6]} Normal pressure glaucoma (NPG) [MIM:606657]: A primary glaucoma characterized by intraocular pression consistently within the statistically normal population range. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.^[7] Amyotrophic lateral sclerosis 12 (ALS12) [MIM:613435]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Note=The disease is caused by mutations affecting the gene represented in this entry.^[8]

Function

[OPTN_HUMAN] Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8. Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation. Negatively regulates the induction of IFNB in response to RNA virus infection. Plays a neuroprotective role in the eye and optic nerve. Probably part of the TNF-alpha signaling pathway that can shift the equilibrium toward induction of cell death. May act by regulating membrane trafficking and cellular morphogenesis via a complex that contains Rab8 and hungtingtin (HD). May constitute a cellular target for adenovirus E3 14.7, an inhibitor of TNF-alpha functions, thereby affecting cell death.^{[9] [10] [11]} [TBK1_HUMAN] Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFN-alpha and IFN-beta. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS or SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1. Phosphorylates Borna disease virus (BDV) P protein.^{[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]}

References

1. ↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
2. ↑ Leung YF, Fan BJ, Lam DS, Lee WS, Tam PO, Chua JK, Tham CC, Lai JS, Fan DS, Pang CP. Different optineurin mutation pattern in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3880-4. PMID:12939304
3. ↑ Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, Johnson AT, Khanna CL, Yamamoto T, Mackey DA, Roos BR, Affatigato LM, Sheffield VC, Stone EM. Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol. 2003 Nov;136(5):904-10. PMID:14597044
4. ↑ Willoughby CE, Chan LL, Herd S, Billingsley G, Noordeh N, Levin AV, Buys Y, Trope G, Sarfarazi M, Heon E. Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3122-30. PMID:15326130 doi:10.1167/iovs.04-0107
5. ↑ Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, Suzuki K, Ideta H, Nakamoto K, Yasuda N, Fujimaki T, Murakami A, Asaoka R, Hotta Y, Tanihara H, Kanamoto T, Mishima H, Fukuchi T, Abe H, Iwata T, Shimada N, Kudoh J, Shimizu N, Mashima Y. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4359-67. PMID:15557444 doi:45/12/4359
6. ↑ Fuse N, Takahashi K, Akiyama H, Nakazawa T, Seimiya M, Kuwahara S, Tamai M. Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population. J Glaucoma. 2004 Aug;13(4):299-303. PMID:15226658
7. ↑ Umeda T, Matsuo T, Nagayama M, Tamura N, Tanabe Y, Ohtsuki H. Clinical relevance of optineurin sequence alterations in Japanese glaucoma patients. Ophthalmic Genet. 2004 Jun;25(2):91-9. PMID:15370540 doi:10.1080/13816810490514298
8. ↑ Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-6. doi: 10.1038/nature08971. Epub 2010 Apr 28. PMID:20428114 doi:10.1038/nature08971
9. ↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
10. ↑ Sahlender DA, Roberts RC, Arden SD, Spudich G, Taylor MJ, Luzio JP, Kendrick-Jones J, Buss F. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol. 2005 Apr 25;169(2):285-95. Epub 2005 Apr 18. PMID:15837803 doi:10.1083/jcb.200501162
11. ↑ Mankouri J, Fragkoudis R, Richards KH, Wetherill LF, Harris M, Kohl A, Elliott RM, Macdonald A. Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. PLoS Pathog. 2010 Feb 19;6(2):e1000778. doi: 10.1371/journal.ppat.1000778. PMID:20174559 doi:10.1371/journal.ppat.1000778
12. ↑ Pomerantz JL, Baltimore D. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 1999 Dec 1;18(23):6694-704. PMID:10581243 doi:10.1093/emboj/18.23.6694
13. ↑ Tojima Y, Fujimoto A, Delhase M, Chen Y, Hatakeyama S, Nakayama K, Kaneko Y, Nimura Y, Motoyama N, Ikeda K, Karin M, Nakanishi M. NAK is an IkappaB kinase-activating kinase. Nature. 2000 Apr 13;404(6779):778-82. PMID:10783893 doi:10.1038/35008109
14. ↑ Kishore N, Huynh QK, Mathialagan S, Hall T, Rouw S, Creely D, Lange G, Caroll J, Reitz B, Donnelly A, Boddupalli H, Combs RG, Kretzmer K, Tripp CS. IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. J Biol Chem. 2002 Apr 19;277(16):13840-7. Epub 2002 Feb 11. PMID:11839743 doi:10.1074/jbc.M110474200
15. ↑ Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003 May;4(5):491-6. PMID:12692549 doi:10.1038/ni921
16. ↑ Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003 May 16;300(5622):1148-51. Epub 2003 Apr 17. PMID:12702806 doi:10.1126/science.1081315
17. ↑ Mori M, Yoneyama M, Ito T, Takahashi K, Inagaki F, Fujita T. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J Biol Chem. 2004 Mar 12;279(11):9698-702. Epub 2003 Dec 31. PMID:14703513 doi:10.1074/jbc.M310616200
18. ↑ Kuai J, Wooters J, Hall JP, Rao VR, Nickbarg E, Li B, Chatterjee-Kishore M, Qiu Y, Lin LL. NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach. J Biol Chem. 2004 Dec 17;279(51):53266-71. Epub 2004 Oct 13. PMID:15485837 doi:M411037200
19. ↑ Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem. 2004 Dec 31;279(53):55633-43. Epub 2004 Oct 15. PMID:15489227 doi:10.1074/jbc.M409825200
20. ↑ tenOever BR, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh WC, Lin R, Hiscott J. Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J Virol. 2004 Oct;78(19):10636-49. PMID:15367631 doi:10.1128/JVI.78.19.10636-10649.2004
21. ↑ Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008 Aug 6;27(15):2135-46. doi: 10.1038/emboj.2008.126. Epub 2008 Jun 26. PMID:18583960 doi:10.1038/emboj.2008.126
22. ↑ Da Q, Yang X, Xu Y, Gao G, Cheng G, Tang H. TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. J Immunol. 2011 Mar 1;186(5):3023-30. doi: 10.4049/jimmunol.1000262. Epub 2011, Jan 26. PMID:21270402 doi:10.4049/jimmunol.1000262
23. ↑ Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6474-9. doi:, 10.1073/pnas.1016132108. Epub 2011 Apr 4. PMID:21464307 doi:10.1073/pnas.1016132108
24. ↑ Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dotsch V, Bumann D, Dikic I. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011 Jul 8;333(6039):228-33. doi: 10.1126/science.1205405. Epub 2011 May, 26. PMID:21617041 doi:10.1126/science.1205405
25. ↑ Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701. PMID:21138416 doi:10.1042/BJ20101701
26. ↑ Li F, Xie X, Wang Y, Liu J, Cheng X, Guo Y, Gong Y, Hu S, Pan L. Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins. Nat Commun. 2016 Sep 13;7:12708. doi: 10.1038/ncomms12708. PMID:27620379 doi:http://dx.doi.org/10.1038/ncomms12708