TY - JOUR
T1 - Linear ubiquitination of cFLIP induced by LUBAC contributes to TNF-induced apoptosis
AU - Tang, Yong
AU - Joo, Donghyun
AU - Liu, Guangna
AU - Tu, Hailin
AU - You, Jeffrey
AU - Jin, Jianping
AU - Zhao, Xueqiang
AU - Hung, Mien Chie
AU - Lin, Xin
N1 - Publisher Copyright:
© 2018 Tang et al.
PY - 2018/12/28
Y1 - 2018/12/28
N2 - The linear ubiquitin chain assembly complex (LUBAC) regulates NF-B activation by modifying proteins with linear (M1-linked) ubiquitination chains. Although LUBAC also regulates the apoptosis pathway, the precise mechanism by which LUBAC regulates apoptosis remains not fully defined. Here, we report that LUBAC-mediated M1-linked ubiquitination of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptotic molecule, contributes to tumor necrosis factor (TNF) -induced apoptosis. We found that deficiency of RNF31, the catalytic subunit of the LUBAC complex, promoted cFLIP degradation in a proteasome-dependent manner. Moreover, we observed RNF31 directly interact with cFLIP, and LUBAC further conjugated M1-linked ubiquitination chains at Lys-351 and Lys-353 of cFLIP to stabilize cFLIP, thereby protecting cells from TNF-induced apoptosis. Together, our study identifies a new substrate of LUBAC and reveals a new molecular mechanism through which LUBAC regulates TNF-induced apoptosis via M1-linked ubiquitination.
AB - The linear ubiquitin chain assembly complex (LUBAC) regulates NF-B activation by modifying proteins with linear (M1-linked) ubiquitination chains. Although LUBAC also regulates the apoptosis pathway, the precise mechanism by which LUBAC regulates apoptosis remains not fully defined. Here, we report that LUBAC-mediated M1-linked ubiquitination of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptotic molecule, contributes to tumor necrosis factor (TNF) -induced apoptosis. We found that deficiency of RNF31, the catalytic subunit of the LUBAC complex, promoted cFLIP degradation in a proteasome-dependent manner. Moreover, we observed RNF31 directly interact with cFLIP, and LUBAC further conjugated M1-linked ubiquitination chains at Lys-351 and Lys-353 of cFLIP to stabilize cFLIP, thereby protecting cells from TNF-induced apoptosis. Together, our study identifies a new substrate of LUBAC and reveals a new molecular mechanism through which LUBAC regulates TNF-induced apoptosis via M1-linked ubiquitination.
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U2 - 10.1074/jbc.RA118.005449
DO - 10.1074/jbc.RA118.005449
M3 - Article
C2 - 30361438
AN - SCOPUS:85059234905
SN - 0021-9258
VL - 293
SP - 20062
EP - 20072
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -