title: LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection.
abstract: Almost all viral pathogens utilize a cytoskeleton for their entry and intracellular transport. In HIV-1 infection, binding of the virus to blood resting CD4 T cells initiates a temporal course of cortical actin polymerization and depolymerization, a process mimicking the chemotactic response initiated from chemokine receptors. The actin depolymerization has been suggested to promote viral intracellular migration through cofilin-mediated actin treadmilling. However, the role of the virus-mediated actin polymerization in HIV infection is unknown, and the signaling molecules involved remain unidentified. Here we describe a pathogenic mechanism for triggering early actin polymerization through HIV-1 envelope-mediated transient activation of the LIM domain kinase (LIMK), a protein that phosphorylates cofilin. We demonstrate that HIV-mediated LIMK activation is through gp120-triggered transient activation of the Rack-PAK-LIMK pathway, and that knockdown of LIMK through siRNA decreases filamentous actin, increases CXCR4 trafficking, and diminishes viral DNA synthesis. These results suggest that HIV-mediated early actin polymerization may directly regulate the CXCR4 receptor during viral entry and is involved in viral DNA synthesis. Furthermore, we also demonstrate that in resting CD4 T cells, actin polymerization can be triggered through transient treatment with a pharmacological agent, okadaic acid, that activates LIMK and promotes HIV latent infection of resting CD4 T cells. Taken together, our results suggest that HIV hijacks LIMK to control the cortical actin dynamics for the initiation of viral infection of CD4 T cells.
authors.affiliation: Department of Molecular and Microbiology, George Mason University, Manassas, Virginia 20110, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Vorster
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: Alyson
authors.initials: A
authors.lastname: Yoder
authors.forename: Weifeng
authors.initials: W
authors.lastname: Wang
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xuehua
authors.initials: X
authors.lastname: Xu
authors.forename: Dongyang
authors.initials: D
authors.lastname: Yu
authors.forename: Mark
authors.initials: M
authors.lastname: Spear
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000378:metabolism*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000199:Actins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D019319:Okadaic Acid; C515892:LIMK1 protein, human; D054461:Lim Kinases