HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1

Anand, Appakkudal R.; Prasad, Anil; Bradley, Ritu R.; Deol, Yadwinder S.; Tirumuru, Nagaraja; Ren, Xianghui; Terwilliger, Ernest F.; Ganju, Ramesh K.

doi:10.1182/blood-2009-02-206342

Cited by 37 publications

(55 citation statements)

References 48 publications

(60 reference statements)

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“…Activated Cdc42 induces complexing of Wasp, LSP1, and the Arp2/3 complex with β-actin, thereby enhancing podosome formation and migration of immature dendritic cells. 196,197 Also, through targeting of Vav and Rac1 signaling, recombinant Nef stimulates maturation of immature human DC and increased clustering with and activation of CD4+ T cells, which has been hypothesized to increase viral transmission. 198,199 On the other hand, in a murine DC line stably expressing Nef, the Nef-PAK2 connection was found to inhibit DC maturation and antigen presentation, which may impair development of antiviral immunity in vivo.…”

Section: Dendritic Cellsmentioning

confidence: 99%

Rho’ing in and out of cells

2014

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These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

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Section: Dendritic Cellsmentioning

confidence: 99%

Rho’ing in and out of cells

2014

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“…3 This mode of cell-to-cell propagation of the pathogen across the DC-T cell infectious synapse may confer several advantages to the virus as it offers a faster propagation as well as some level of immune evasion. 4,5 Despite many advances in the understanding of transfer of HIV-1 infection from DCs to T cells, 2,3,[6][7][8][9][10][11][12] not much is known yet about the structural and biochemical mechanisms that are responsible for viral transfer by cell-to-cell transmission.…”

Section: Introductionmentioning

confidence: 99%

“…12 Alternatively, gp120-mediated activation of Pyk2, p38 MAP kinase, and LSP1 has also recently been implicated in DC migration after HIV-1 binding. 10 Other signaling cascades in DCs, such as the Erk pathway 11,12 and the Src/Syk pathway, 15 might also be activated by HIV-1. These signaling programs triggered by DC-SIGN engagement suggest potential links between C-type lectin receptors activation on DCs and cytoskeletal remodeling.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 activates Cdc42 and induces membrane extensions in immature dendritic cells to facilitate cell-to-cell virus propagation

Nikolic

Lehmann

Felts

et al. 2011

Blood

113

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“…In neutrophils, LSP1 is phosphorylated by the activation of p38 MAPK downstream of soluble chemoattractant receptor signaling and then colocalizes with F-actin, thus contributing to the stability of its polarization during chemotaxis (16,17). A similar mechanism was observed in migrating dendritic cells, which showed enhanced phosphorylation of LSP1 concomitant with increased actin association in response to the viral protein gp120 (18). Surprisingly, these mechanisms are not operative in activation of endothelial LSP1, which was recently shown to be phosphorylated following ICAM-1-mediated adhesive engagement, but not by cytokine or chemokine stimulation alone (19).…”

mentioning

confidence: 81%

“…Targeted gene silencing was achieved by a 48-h transfection of the cells with small interfering RNA (siRNA) specifically targeting LSP1 (Santa Cruz Biotechnology, Dallas, TX) or GATA-2 (Santa Cruz Biotechnology) and with siRNA transfection medium and reagent (Santa Cruz Biotechnology) according to the manufacturer's protocol (18). The control cells were transfected with negative control scrambled siRNA (Santa Cruz Biotechnology) having no homology to any known RNA sequence.…”

Section: Gene Silencing and Overexpressionmentioning

confidence: 99%

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Hossain

Qadri

et al. 2015

The Journal of Immunology

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During inflammation, leukocyte–endothelial cell interactions generate molecular signals that regulate cell functions. The Ca2+- and F-actin–binding leukocyte-specific protein 1 (LSP1) expressed in leukocytes and nonhematopoietic endothelial cells is pivotal in regulating microvascular permeability and leukocyte recruitment. However, cell-specific function of LSP1 during leukocyte recruitment remains elusive. Using intravital microscopy of cremasteric microvasculature of chimeric LSP1-deficient mice, we show that not neutrophil but endothelial LSP1 regulates neutrophil transendothelial migration and extravascular directionality without affecting the speed of neutrophil migration in tissue in response to CXCL2 chemokine gradient. The expression of PECAM-1–sensitive α6β1 integrins on the surface of transmigrated neutrophils was blunted in mice deficient in endothelial LSP1. Functional blocking studies in vivo and in vitro elucidated that α6β1 integrins orchestrated extravascular directionality but not the speed of neutrophil migration. In LSP1-deficient mice, PECAM-1 expression was reduced in endothelial cells, but not in neutrophils. Similarly, LSP1-targeted small interfering RNA silencing in murine endothelial cells mitigated mRNA and protein expression of PECAM-1, but not ICAM-1 or VCAM-1. Overexpression of LSP1 in endothelial cells upregulated PECAM-1 expression. Furthermore, the expression of transcription factor GATA-2 that regulates endothelial PECAM-1 expression was blunted in LSP1-deficient or LSP1-silenced endothelial cells. The present study unravels endothelial LSP1 as a novel cell-specific regulator of integrin α6β1-dependent neutrophil extravascular chemotactic function in vivo, effective through GATA-2–dependent transcriptional regulation of endothelial PECAM-1 expression.

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HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1

Cited by 37 publications

References 48 publications

Rho’ing in and out of cells

Rho’ing in and out of cells

HIV-1 activates Cdc42 and induces membrane extensions in immature dendritic cells to facilitate cell-to-cell virus propagation

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

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