Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.

The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in...

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Autores principales:	Ananthamurthy Nagabhushana, Megha Bansal, Ghanshyam Swarup
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4cd6f29d210840b79b67394f60e202f9
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spelling	oai:doaj.org-article:4cd6f29d210840b79b67394f60e202f92021-11-18T06:57:45ZOptineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.1932-620310.1371/journal.pone.0017477https://doaj.org/article/4cd6f29d210840b79b67394f60e202f92011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408173/?tool=EBIhttps://doaj.org/toc/1932-6203The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-κB activation. It competes with NEMO (NF-κB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-κB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor α (TNFα)-induced NF-κB activation. CYLD mediated inhibition of TNFα-induced NF-κB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFα-induced NF-κB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-κB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP.Ananthamurthy NagabhushanaMegha BansalGhanshyam SwarupPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17477 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
description	The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-κB activation. It competes with NEMO (NF-κB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-κB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor α (TNFα)-induced NF-κB activation. CYLD mediated inhibition of TNFα-induced NF-κB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFα-induced NF-κB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-κB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP.
format	article
author	Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup
author_facet	Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup
author_sort	Ananthamurthy Nagabhushana
title	Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
title_short	Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
title_full	Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
title_fullStr	Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
title_full_unstemmed	Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
title_sort	optineurin is required for cyld-dependent inhibition of tnfα-induced nf-κb activation.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4cd6f29d210840b79b67394f60e202f9
work_keys_str_mv	AT ananthamurthynagabhushana optineurinisrequiredforcylddependentinhibitionoftnfainducednfkbactivation AT meghabansal optineurinisrequiredforcylddependentinhibitionoftnfainducednfkbactivation AT ghanshyamswarup optineurinisrequiredforcylddependentinhibitionoftnfainducednfkbactivation
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Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.

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