APOBEC3G is degraded by the proteasomal pathway in a Vif-dependent manner without being polyubiquitylated.
Although the covalent attachment of a polyubiquitin is the prevailing paradigm for entry into proteasomes, accumulating evidence suggests that poorly defined ubiquitin-free pathways also degrade proteins. The cytidine deaminase APOBEC3G (A3G) potently inhibits human immunodeficiency virus type 1 replication by disrupting viral reverse transcription. However, human immunodeficiency virus type 1 produces a viral infectivity factor (Vif) to destroy this antiretroviral protein. It was shown that Vif binds to both A3G and a Cullin 5 ubiquitin-protein isopeptide ligase. It is currently accepted that this enzyme polyubiquitylates A3G on lysine residues, resulting in its degradation by proteasomes. Here, we find that A3G without ubiquitylation is still degraded by proteasomes in a Vif-dependent manner. We further show that Vif is polyubiquitylated and that this event could be critical for A3G proteasomal degradation. Thus, A3G is degraded by a novel pathway that might involve ubiquitylation of one protein and then targets a second binding partner for proteasomal entry and degradation. We propose that instead of triggering A3G polyubiquitylation, polyubiquitylated Vif might serve as a vehicle to transport A3G into proteasomes for degradation.
Dang
Ying
Y
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824-4320, USA.
Siew
Lai Mun
LM
Zheng
Yong-Hui
YH
D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D003564:Cytidine Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013379:Substrate Specificity; D054875:Ubiquitination; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C496871:CUL5 protein, human; D044842:Cullin Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D046988:Proteasome Endopeptidase Complex; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase