Abstract
HIV-1 Vpu interacts with CD4 in the endoplasmic reticulum and triggers CD4 degradation, presumably by proteasomes. Human beta TrCP identified by interaction with Vpu connects CD4 to this proteolytic machinery, and CD4-Vpu-beta TrCP ternary complexes have been detected by coimmunoprecipitation. beta TrCP binding to Vpu and its recruitment to membranes require two phosphoserine residues in Vpu essential for CD4 degradation. In beta TrCP, WD repeats at the C terminus mediate binding to Vpu, and an F box near the N terminus is involved in interaction with Skp1p, a targeting factor for ubiquitin-mediated proteolysis. An F-box deletion mutant of beta TrCP had a dominant-negative effect on Vpu-mediated CD4 degradation. These data suggest that beta TrCP and Skp1p represent components of a novel ER-associated protein degradation pathway that mediates CD4 proteolysis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Binding Sites / immunology
-
CD4 Antigens / metabolism*
-
Cell Cycle Proteins / metabolism
-
Endoplasmic Reticulum / chemistry
-
Endoplasmic Reticulum / metabolism*
-
Endoplasmic Reticulum / virology
-
GTP-Binding Proteins / chemistry
-
GTP-Binding Proteins / genetics*
-
GTP-Binding Proteins / metabolism
-
HIV-1*
-
Human Immunodeficiency Virus Proteins
-
Humans
-
Jurkat Cells
-
Molecular Sequence Data
-
Mutagenesis / physiology
-
Repetitive Sequences, Nucleic Acid
-
S-Phase Kinase-Associated Proteins
-
Sequence Homology, Amino Acid
-
Serine / metabolism
-
Ubiquitins / metabolism
-
Viral Regulatory and Accessory Proteins / metabolism*
-
beta-Transducin Repeat-Containing Proteins
Substances
-
BTRC protein, human
-
CD4 Antigens
-
Cell Cycle Proteins
-
Human Immunodeficiency Virus Proteins
-
S-Phase Kinase-Associated Proteins
-
Ubiquitins
-
Viral Regulatory and Accessory Proteins
-
beta-Transducin Repeat-Containing Proteins
-
vpu protein, Human immunodeficiency virus 1
-
Serine
-
GTP-Binding Proteins