Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.
As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.
Choi
Won-Tak
WT
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Kaul
Marcus
M
Kumar
Santosh
S
Wang
Jun
J
Kumar
I M Krishna
IM
Dong
Chang-Zhi
CZ
An
Jing
J
Lipton
Stuart A
SA
Huang
Ziwei
Z
D015526:AIDS Dementia Complex / Q000188:drug therapy*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D065100:CCR5 Receptor Antagonists; D018925:Chemokines / Q000494:pharmacology*; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000187:drug effects; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D065100:CCR5 Receptor Antagonists; D018925:Chemokines; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D019718:Receptors, CXCR4; D048051:p38 Mitogen-Activated Protein Kinases