β-Arrestin 2 Promotes Hepatocyte Apoptosis by Inhibiting Akt Protein

Abstract

Recent studies reveal that multifunctional protein ␤-arrestin 2 (Arrb2) modulates cell apoptosis. Survival and various aspects of liver injury were investigated in WT and Arrb2 KO mice after bile duct ligation (BDL). We found that deficiency of Arrb2 enhances survival and attenuates hepatic injury and fibrosis. Following BDL, Arrb2-deficient mice as compared with WT controls displayed a significant reduction of hepatocyte apoptosis as demonstrated by the TUNEL assay. Following BDL, the levels of phospho-Akt and phospho-glycogen synthase kinase 3␤ (GSK3␤) in the livers were significantly increased in Arrb2 KO compared with WT mice, although p-p38 increased in WT but not in Arrb2-deficient mice. Inhibition of GSK3␤ following BDL decreases hepatic apoptosis and decreased p-p38 in WT mice but not in Arrb2 KO mice. Activation of Fas receptor with Jo2 reduces phospho-Akt and increases apoptosis in WT cells and WT mice but not in Arrb2-deficient cells and Arrb2-deficient mice. Consistent with direct interaction of Arrb2 with and regulating Akt phosphorylation, the expression of a full-length or N terminus but not the C terminus of Arrb2 reduces Akt phosphorylation and coimmunoprecipates with Akt. These results reveal that the protective effect of deficiency of Arrb2 is due to loss of negative regulation of Akt due to BDL and decreased downstream GSK3␤ and p38 MAPK signaling pathways.

MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2

“…Arrb2, a multifunctional adapter protein, plays important roles in both regulations of immune activation and cardiac function [ 14 – 16 ]. Arrb2 interacts with the adaptor TRAF6 to negatively regulate Toll-like receptor signaling in innate immunity [ 41 ].…”

“…Heart tissues were immersion-fixed in 4% buffered paraformaldehyde, embedded in paraffin. ICH was performed with a Diaminobenzidine (DAB) Histochemistry kit (Molecular Probes, Invitrogen, CA) according to the manufacturer's protocol and our previous studies [ 14 , 46 ]. Briefly, following antigen retrieval with 1mM EDTA (pH 8.0), deparaffinized sections were incubated in 1% Blocking Reagent solution for 1 h at 37°C and then stained with anti-ICAM-1 (1:50 dilution; Santa Cruz Biotechnology) and anti-VCAM-1 (1:50 dilution; Santa Cruz Biotechnology) respectively, overnight at 4°C.…”

“…β-arrestin 2 (Arrb2), a multifunctional regulator of G protein-coupled receptors with especially high expression in cardiovascular tissues, can modulate a diverse array of biological processes [ 14 , 15 ]. Increasing evidence suggests that Arrb2 plays a crucial role in regulating systemic immune responses and the kinetics of Arrb2-mediated signaling is tissue-dependent [ 15 , 16 ].…”

β-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38

“…The scaffolding protein β-arrestin 2 has been conventionally associated with receptor internalization. β-arrestin 2 can scaffold different sets of molecules that determine different and even opposite effects on the same signaling cascade dependent on the receptor activated [29], [30].…”

β-Arrestin 2 Promotes Hepatocyte Apoptosis by Inhibiting Akt Pathway in Alcoholic Liver Disease

“…It is well documented that multifunctional adaptor β-arrestin 2 (Arrb2) modulates cell apoptosis and it may have either a pro- or anti-apoptotic effect in different diseases. For instance, Arrb2 promotes hepatocyte apoptosis in bile duct ligation (BDL) while blocking hepatic stellate cells (HSCs) apoptosis in liver fibrosis ( Sun et al, 2013 ; Yin et al, 2016 ; Zhang et al, 2017 ). However, the role of Arrb2 in modulating apoptosis during ALD remains unclear.…”