PuSH - Publication Server of Helmholtz Zentrum München: OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.

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Keusekotten, K.* ; Elliott, P.R.* ; Glockner, L. ; Fiil, B.K.* ; Damgaard, R.B.* ; Kulathu, Y.* ; Wauer, T.* ; Hospenthal, M.K.* ; Gyrd-Hansen, M.* ; Krappmann, D. ; Hofmann, K.* ; Komander, D.*

OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.

Cell 153, 1312-1326 (2013)

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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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