Figure 1.
Chemokine receptor signaling pathways.
SDF-1 binding to CXCR4 or RANTES/MIP-1α/MIP-1β binding to CCR5 activates G proteins (Gα particularly Gαi, Gαq, and Gβγ) and multiple downstream pathways. (A) Gαq activates phospholipases such as phospholipase C-γ (PLC-γ), which hydrolyzes phosphatidylinositol-4,5-biphosphate (PIP2) to generate inositol triphosphate (IP3) and diacylglyerol (DAG), triggering calcium influx and the activation of kinases such as protein kinase C (PKC). (B) Gαi activates phospholipases, phosphodiesterases, and the lipid kinase PI3K via Src-family kinases. Gβγ also activates PI3Kγ. PI3K activation stimulates downstream targets such as protein kinase B (PKB/Akt), NF-κB, mitogen/extracellular signal-regulated kinase (MEK-1), and extracellular signal-regulated kinase (ERK1/2). PI3K also triggers the tyrosine phosphorylation of focal adhesion complex components such as proline-rich tyrosine kinase (Pyk2), paxillin, Crk, and p130Cas. (C) GTP-bound Gβγ stimulates guanine nucleotide exchange factors (GEFs) such as TIAM1 and PREX1 specific for the Rho family GTPases (Rac/CDC42/RhoA). These GTPases activate pathways regulating cytoskeleton: Rac activates p21-activated kinase (PAK), which then activates LIM kinase (LIMK), leading to cofilin phosporylation and actin polymerization. CDC42 promotes actin assembly through the Wiskott-Aldrich Syndrome family protein (WASP) and actin-nucleating protein Arp2/3. RhoA activates Rho kinase (ROCK) , leading to myosin light-chain (MLC) phosporylation and microtubule rearrangement. (D) SDF-1 may also trigger Gαi-independent activation of the JAK-STAT pathways.
Figure 2.
Components of the chemokine coreceptor signaling pathways activated by HIV-1 envelope.
HIV-1 gp120 binding to CXCR4 or CCR5 activates a number of signaling molecules common to chemokine-mediated signaling pathways, including (A) PLC-γ-dependent calcium flux and NFAT nuclear translocation; (B) PI3K-dependent activation of FAK, PyK2, AKT, and ERK1/2; (C) the downstream targets of the Rho family GTPases such as LIMK1 and cofilin for actin rearrangement.
Figure 3.
HIV-1 envelope-CXCR4 signaling triggers cofilin activation to promote cortical actin dynamics and HIV nuclear migration.
(A) HIV-1 envelope binding to CD4 and the chemokine coreceptor, CXCR4, triggers membrane fusion and signaling transduction. The initial viral contact with CD4 and then CXCR4 may trigger rapid actin polymerization to facilitate CD4/CXCR4 cocapping for fusion and entry. Following fusion, the viral preintegration complex (PIC) may be directly anchored onto F-actin to facilitate reverse transcription. Subsequent actin activity mediated by cofilin activation through CXCR4 promotes viral nuclear migration. (B) Model of HIV PIC migration along the cortical actin filaments. It is possible that cofilin activation increases actin treadmilling, which promotes the movement of the viral PIC across the cortical actin barrier, allowing PIC to gain access to the perinuclear or nuclear region. The number is arbitrarily assigned to an actin monomer to demonstrate the actin movement during treadmilling. (Figure 3 is modified from [44] with permission).