Id-1 induces proteasome-dependent degradation of the HBX protein.
Id-1 is a member of the HLH protein family that regulates a wide range of cellular processes such as cell proliferation, apoptosis, senescence and overexpression of Id-1 was recently suggested to play roles in the development and progression of different cancers. Previously, Id-1 was shown to physically interact with the viral protein E1A. Meanwhile, Id-1 expression was found to be regulated by several of the virus-encoded proteins, suggesting that Id-1 may be a common cellular target of the viral proteins. Here, we report that Id-1 interacts with the Hepatitis-B virus (HBV)-encoded protein HBX and regulates its stability in hepatocellular carcinoma (HCC) cells. We found that in HCC cells, ectopic Id-1 expression significantly decreased the half-life of the HBX protein, indicating that HBX is destabilized by Id-1. Meanwhile, the Id-1-induced HBX degradation was found to be inhibited by treatment with proteasome inhibitor, suggesting that this process is mediated through the proteasome pathway. Interestingly, while Id-1 did not induce HBX-ubiquitination, we found that removal of all the lysine residues of the HBX protein protects it from the effect of Id-1, indicating that ubiquitination is still required for the Id-1-mediated HBX degradation. Meanwhile, we found that Id-1 binds to the proteasome subunit C8 and facilitates its interaction with the HBX protein and disruption of this interaction completely abolishes the negative effect of Id-1 on HBX protein stability. Taken together, our results demonstrated a novel function of Id-1 in regulating HBX protein stability through interaction with the proteasome.
Ling
Ming-Tat
MT
Cancer Biology Group, Department of Anatomy, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China.
Chiu
Yung-Tuen
YT
Lee
Terence Kin Wah
TK
Leung
Steve Chin Lung
SC
Fung
Maggie Ka Lai
MK
Wang
Xianghong
X
Wong
Kwong Fai
KF
Wong
Yong-Chuan
YC
D045744:Cell Line, Tumor; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D013816:Thermodynamics; D015534:Trans-Activators; D054875:Ubiquitination; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000378:metabolism*
D051798:Inhibitor of Differentiation Protein 1; D021122:Protein Subunits; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D046988:Proteasome Endopeptidase Complex