Mitogen-activated protein kinase phosphorylates and regulates the HIV-1 Vif protein

被引:84
作者
Yang, XY
Gabuzda, D
机构
[1] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.273.45.29879
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The human immunodeficiency virus type 1 (HIV-1) Vif protein plays a critical role in virus replication and infectivity. Here we show that Vif is phosphorylated and regulated by p44/42 mitogen-activated protein kinase (MAPK). Vif phosphorylation by MAPK was demonstrated in vitro as well as in vivo and was shown to occur on serine and threonine residues. Two-dimensional tryptic phosphopeptide mapping indicated that Vif is phosphorylated by MAPK on the same sites in vitro and in vivo. Radioactive peptide sequencing identified two phosphorylation sites, Thr(96) and Ser(165). These phosphorylation sites do not correspond to the known optimum consensus sequences for phosphorylation by MAPK (PX(S/T)P) nor to the minimum consensus sequence ((S/ T)P), indicating that MAPK can phosphorylate proteins at sites other than those containing the PX(SPT)P or (S/T)P motifs. Synthetic Vif peptides corresponding to the local sequences of the phosphorylation sites were not phosphorylated by MAPK, suggesting that recognition of these sites by MAPK is likely to require structural determinants outside the phosphorylation site. Mutations of the Thr96 site, which is conserved among Vif sequences from HIV-1, HIV-2, and SIV, resulted in significant loss of Vif activity and inhibition of HIV-1 replication. These results suggest that MAPK plays a direct role in regulating HIV-1 replication and infectivity by phosphorylating Vif and identify a novel mechanism for activation of HIV-1 replication by mitogens and other extracellular stimuli.
引用
收藏
页码:29879 / 29887
页数:9
相关论文
共 59 条
[11]   HOW MAP KINASES ARE REGULATED [J].
COBB, MH ;
GOLDSMITH, EJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (25) :14843-14846
[12]   THE HUMAN IMMUNODEFICIENCY VIRUS REV PROTEIN IS A NUCLEAR PHOSPHOPROTEIN [J].
COCHRANE, A ;
KRAMER, R ;
RUBEN, S ;
LEVINE, J ;
ROSEN, CA .
VIROLOGY, 1989, 171 (01) :264-266
[13]   FUNCTIONAL-SIGNIFICANCE OF PHOSPHORYLATION TO THE HUMAN IMMUNODEFICIENCY VIRUS REV PROTEIN [J].
COCHRANE, AW ;
GOLUB, E ;
VOLSKY, D ;
RUBEN, S ;
ROSEN, CA .
JOURNAL OF VIROLOGY, 1989, 63 (10) :4438-4440
[14]   The critical role of p38 MAP kinase in T cell HIV-I replication [J].
Cohen, PS ;
Schmidtmayerova, H ;
Dennis, J ;
Dubrovsky, L ;
Sherry, B ;
Wang, HC ;
Bukrinsky, M ;
Tracey, KJ .
MOLECULAR MEDICINE, 1997, 3 (05) :339-346
[15]   Physical and functional interaction of Nef with Lck - HIV-1 Nef-induced T-cell signaling defects [J].
Collette, Y ;
Dutartre, H ;
Benziane, A ;
RamosMorales, F ;
Benarous, R ;
Harris, M ;
Olive, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (11) :6333-6341
[16]   PERIPHERAL-BLOOD MONONUCLEAR-CELLS PRODUCE NORMAL AMOUNTS OF DEFECTIVE VIF(-) HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PARTICLES WHICH ARE RESTRICTED FOR THE PRERETROTRANSCRIPTION STEPS [J].
COURCOUL, M ;
PATIENCE, C ;
REY, F ;
BLANC, D ;
HARMACHE, A ;
SIRE, J ;
VIGNE, R ;
SPIRE, B .
JOURNAL OF VIROLOGY, 1995, 69 (04) :2068-2074
[17]   ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES BY VASCULAR ENDOTHELIAL GROWTH-FACTOR AND BASIC FIBROBLAST GROWTH-FACTOR IN CAPILLARY ENDOTHELIAL-CELLS IS INHIBITED BY THE ANTIANGIOGENIC FACTOR 16-KDA N-TERMINAL FRAGMENT OF PROLACTIN [J].
DANGELO, G ;
STRUMAN, I ;
MARTIAL, J ;
WEINER, RI .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (14) :6374-6378
[18]  
DAVIS RJ, 1993, J BIOL CHEM, V268, P14553
[19]   THE SOR GENE OF HIV-1 IS REQUIRED FOR EFFICIENT VIRUS TRANSMISSION INVITRO [J].
FISHER, AG ;
ENSOLI, B ;
IVANOFF, L ;
CHAMBERLAIN, M ;
PETTEWAY, S ;
RATNER, L ;
GALLO, RC ;
WONGSTAAL, F .
SCIENCE, 1987, 237 (4817) :888-893
[20]   The Ras-Raf pathway is activated in human immunodeficiency virus-infected monocytes and participates in the activation of NF-kappa B [J].
Folgueira, L ;
Algeciras, A ;
MacMorran, WS ;
Bren, GD ;
Paya, CV .
JOURNAL OF VIROLOGY, 1996, 70 (04) :2332-2338