HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells.
Binding of HIV type 1 (HIV-1) envelope glycoproteins to the surface of a CD4(+) T cell transduces intracellular signals through the primary envelope receptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-CD4(+) cell interactions increase rates of apoptosis in peripheral blood mononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes, recombinant HIV-1 envelope proteins induce the activation of caspase-3 and caspase-6, which belong to a family of cysteine proteases that, upon activation, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes apoptosis. En-velope treatment of lymphocytes led to the cleavage of FAK in a manner consistent with caspase-mediated cleavage.
Cicala
C
C
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. CCicala@nih.gov
Arthos
J
J
Rubbert
A
A
Selig
S
S
Wildt
K
K
Cohen
O J
OJ
Fauci
A S
AS
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000821:virology*; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015686:Gene Products, env / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D015686:Gene Products, env; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases