β-arrestin 2 regulates Toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3β.
Toll-like receptor 4 (TLR4), a key member of the TLR family, has been well characterized by its function in the induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events by an unknown mechanism has been the focus of great interest. Our investigation found that TLR4 promoted apoptotic signalling by affecting the glycogen synthase kinase-3beta (GSK-3beta) pathway in a serum-deprivation-induced apoptotic paradigm. Serum deprivation induces GSK-3beta activation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 but greatly attenuated by beta-arrestin 2, another critical molecule implicated in TLR4-mediated immune responses. Our data suggest that the association of beta-arrestin 2 with GSK-3beta contributes to the stabilization of phospho-GSK-3beta, an inactive form of GSK-3beta. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis by beta-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3beta activation thereby deteriorating serum-deprivation-induced apoptosis; beta-arrestin 2 represents an inhibitory effect on the TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3beta.
Li
Hui
H
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Sun
Xiuli
X
LeSage
Gene
G
Zhang
Yi
Y
Liang
Zhihou
Z
Chen
Jixiang
J
Hanley
Gregory
G
He
Lei
L
Sun
Shenggang
S
Yin
Deling
D
D000818:Animals; D017209:Apoptosis; D019390:Arrestins / Q000378:metabolism*; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3