Functional interaction between the cytoplasmic leucine-zipper domain of HIV-1 gp41 and p115-RhoGEF.
The long cytoplasmic tail of the human immunodeficiency virus (HIV)-1 transmembrane protein gp41 (gp41C) is implicated in the replication and cytopathicity of HIV-1 [1]. Little is known about the specific functions of gp41C, however. HIV-1 or simian immunodeficiency virus (SIV) mutants with defective gp41C have cell-type- or species-dependent phenotypes [2] [3] [4] [5] [6]. Thus, host factors are implicated in mediating the functions of gp41C. We report here that gp41C interacted with the carboxy-terminal regulatory domain of p115-RhoGEF [7], a specific guanine nucleotide exchange factor (GEF) and activator of the RhoA GTPase, which regulates actin stress fiber formation, activation of serum response factor (SRF) and cell proliferation [8] [9]. We demonstrate that gp41C inhibited p115-mediated actin stress fiber formation and activation of SRF. An amphipathic helix region with a leucine-zipper motif in gp41C is involved in its interaction with p115. Mutations in gp41C leading to loss of interaction with p115 impaired HIV-1 replication in human T cells. These findings suggest that an important function of gp41C is to modulate the activity of p115-RhoGEF and they thus reveal a new potential anti-HIV-1 target.
Zhang
H
H
The Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Wang
L
L
Kao
S
S
Whitehead
I P
IP
Hart
M J
MJ
Liu
B
B
Duus
K
K
Burridge
K
K
Der
C J
CJ
Su
L
L
D000199:Actins / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016350:Leucine Zippers; D009687:Nuclear Proteins / Q000378:metabolism; D011487:Protein Conformation; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor; D013601:T-Lymphocytes; D014779:Virus Replication
C576600:ARHGEF1 protein, human; D000199:Actins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015700:HIV Envelope Protein gp41; D009687:Nuclear Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor