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Suppression of LUBAC ‐mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN
Author(s) -
Takiuchi Tsuyoshi,
Nakagawa Tomoko,
Tamiya Hironari,
Fujita Hiroaki,
Sasaki Yoshiteru,
Saeki Yasushi,
Takeda Hiroyuki,
Sawasaki Tatsuya,
Buchberger Alexander,
Kimura Tadashi,
Iwai Kazuhiro
Publication year - 2014
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12128
Subject(s) - deubiquitinating enzyme , ubiquitin , ubiquitin ligase , biology , microbiology and biotechnology , protein subunit , ubiquitin protein ligases , biochemistry , gene
Linear ubiquitin chains generated by the linear ubiquitin chain assembly complex ( LUBAC ) play an important role in NF ‐κB activation. However, the regulation of linear ubiquitin chain generation by LUBAC is not well characterized. Here, we identified two deubiquitinating enzymes ( DUB s), ovarian tumor DUB with linear linkage specificity ( OTULIN /Gumby/ FAM 105B) and cylindromatosis ( CYLD ) that can cleave linear polyubiquitin chains and interact with LUBAC via the N‐terminal PNG ase/ UBA or UBX ( PUB ) domain of HOIP , a catalytic subunit of LUBAC . HOIP interacts with both CYLD and OTULIN even in unstimulated cells. The interaction of CYLD and OTULIN with HOIP synergistically suppresses LUBAC ‐mediated linear polyubiquitination and NF ‐κB activation. Moreover, introduction of a HOIP mutant unable to bind either deubiquitinase into HOIP ‐null cells augments the activation of NF ‐κB by TNF ‐α stimulation. Thus, the interactions between these two deubiquitinases and the LUBAC ubiquitin ligase are involved in controlling the extent of TNF ‐α‐induced NF ‐κB activation in cells by fine‐tuning the generation of linear ubiquitin chains by LUBAC . The interaction of HOIP with OTULIN is also involved in OTULIN suppressing the canonical Wnt signaling pathway activation by LUBAC . Our observations provide molecular insights into the roles of ligase–deubiquitinase interactions in regulating molecular events resulting from linear ubiquitin conjugation.