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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.
Cell 153, 1312-1326 (2013)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Review
Schlagwörter
Linear Ubiquitin Chains ; Kappa-b Activation ; Immune-responses ; Assembly Complex ; Ligase ; Deubiquitinase ; Inflammation ; Reveals ; Domain ; Recognition
ISSN (print) / ISBN
0092-8674
e-ISSN
1097-4172
Zeitschrift
Cell
Quellenangaben
Band: 153,
Heft: 6,
Seiten: 1312-1326
Verlag
Cell Press
Verlagsort
Cambridge, Mass.
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Signaling and Translation (SAT)