Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN.
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 (DUBs), ovarian tumor DUB with linear linkage specificity (OTULIN/Gumby/FAM105B) and cylindromatosis (CYLD) that can cleave linear polyubiquitin chains and interact with LUBAC via the N-terminal PNGase/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.
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan; Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
Tsuyoshi
T
Takiuchi
Tomoko
T
Nakagawa
Hironari
H
Tamiya
Hiroaki
H
Fujita
Yoshiteru
Y
Sasaki
Yasushi
Y
Saeki
Hiroyuki
H
Takeda
Tatsuya
T
Sawasaki
Alexander
A
Buchberger
Tadashi
T
Kimura
Kazuhiro
K
Iwai
D000074749:Deubiquitinating Enzyme CYLD; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway
D016328:NF-kappa B; D021122:Protein Subunits; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D010450:Endopeptidases; C582107:OTULIN protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD