OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.
The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has no...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2013
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| _version_ | 1797072253006905344 |
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| author | Keusekotten, K Elliott, P Glockner, L Fiil, B Damgaard, R Kulathu, Y Wauer, T Hospenthal, M Gyrd-Hansen, M Krappmann, D Hofmann, K Komander, D |
| author_facet | Keusekotten, K Elliott, P Glockner, L Fiil, B Damgaard, R Kulathu, Y Wauer, T Hospenthal, M Gyrd-Hansen, M Krappmann, D Hofmann, K Komander, D |
| author_sort | Keusekotten, K |
| collection | OXFORD |
| description | The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling. |
| first_indexed | 2024-03-06T23:05:04Z |
| format | Journal article |
| id | oxford-uuid:637c82d2-a2ef-4544-9285-93a30beb3d97 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:05:04Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:637c82d2-a2ef-4544-9285-93a30beb3d972022-03-26T18:13:23ZOTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:637c82d2-a2ef-4544-9285-93a30beb3d97EnglishSymplectic Elements at Oxford2013Keusekotten, KElliott, PGlockner, LFiil, BDamgaard, RKulathu, YWauer, THospenthal, MGyrd-Hansen, MKrappmann, DHofmann, KKomander, DThe linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling. |
| spellingShingle | Keusekotten, K Elliott, P Glockner, L Fiil, B Damgaard, R Kulathu, Y Wauer, T Hospenthal, M Gyrd-Hansen, M Krappmann, D Hofmann, K Komander, D OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title | OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title_full | OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title_fullStr | OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title_full_unstemmed | OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title_short | OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. |
| title_sort | otulin antagonizes lubac signaling by specifically hydrolyzing met1 linked polyubiquitin |
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