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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-03-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408173/?tool=EBI |
| _version_ | 1818722585386418176 |
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| author | Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup |
| author_facet | Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup |
| author_sort | Ananthamurthy Nagabhushana |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T20:56:58Z |
| format | Article |
| id | doaj.art-4cd6f29d210840b79b67394f60e202f9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T20:56:58Z |
| publishDate | 2011-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-4cd6f29d210840b79b67394f60e202f92022-12-21T21:32:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-03-0163e1747710.1371/journal.pone.0017477Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.Ananthamurthy NagabhushanaMegha BansalGhanshyam SwarupThe 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408173/?tool=EBI |
| spellingShingle | Ananthamurthy Nagabhushana Megha Bansal Ghanshyam Swarup Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation. PLoS ONE |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408173/?tool=EBI |
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