HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint.
Accurate chromosomal segregation is monitored by the mitotic checkpoint, and an increased rate of chromosomal missegregation leads to chromosomal instability (CIN). Here, we demonstrate that the HBV X protein (HBx) binds BubR1, a component of the mitotic checkpoint complex and co-localizes with BubR1 at the kinetochores. HBx binding to BubR1 attenuates the association between BubR1 and CDC20, an activator of the anaphase-promoting complex/cyclosome (APC/C) and induces slippage of mitotic arrest in the presence of microtubule poisons. In addition, HBx binding to BubR1 results in the accumulation of lagging chromosomes and chromosome bridges. In contrast, a C-terminally truncated HBx mutant (HBx(1-100)) fails to bind BubR1 and does not cause aberrant chromosomal segregation. This provides a novel mechanism for dysregulation of the mitotic checkpoint by a viral pathogen linking it to the accumulation of chromosomal instability in HBV-associated hepatocarcinogenesis.
Kim
S
S
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
Park
S-Y
SY
Yong
H
H
Famulski
J K
JK
Chae
S
S
Lee
J-H
JH
Kang
C-M
CM
Saya
H
H
Chan
G K
GK
Cho
H
H
D064173:Anaphase-Promoting Complex-Cyclosome; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D018386:Kinetochores; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D008941:Spindle Apparatus; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins
D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases