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Rhoa Effector Activity Modulation of HIV-1 Replication by a Novel

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Rhoa Effector Activity Modulation of HIV-1 Replication by a Novel Modulation of HIV-1 Replication by a Novel RhoA Effector Activity Liping Wang, Hangchun Zhang, Patricia A. Solski, Matthew J. Hart, Channing J. Der and Lishan Su This information is current as of September 24, 2021. J Immunol 2000; 164:5369-5374; ; doi: 10.4049/jimmunol.164.10.5369 http://www.jimmunol.org/content/164/10/5369 Downloaded from References This article cites 52 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/164/10/5369.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Modulation of HIV-1 Replication by a Novel RhoA Effector Activity1 Liping Wang,*‡ Hangchun Zhang,‡§ Patricia A. Solski,†‡ Matthew J. Hart,¶ Channing J. Der,†‡ and Lishan Su2*‡ The RhoA GTPase is involved in regulating actin cytoskeletal organization, gene expression, cell proliferation, and survival. We report here that p115-RhoGEF, a specific guanine nucleotide exchange factor (GEF) and activator of RhoA, modulates HIV-1 replication. Ectopic expression of p115-RhoGEF or G␣13, which activates p115-RhoGEF activity, leads to inhibition of HIV-1 replication. RhoA activation is required and the inhibition affects HIV-1 gene expression. The RhoA effector activity in inhibiting HIV-1 replication is genetically separable from its activities in transformation of NIH3T3 cells, activation of serum response factor, and actin stress fiber formation. These findings reveal that the RhoA signal transduction pathway regulates HIV-1 replication and suggest that RhoA inhibits HIV-1 replication via a novel effector activity. The Journal of Immunology, 2000, 164: 5369–5374. Downloaded from he Rho family of small GTPases (RhoA, Rac1, and proteins (12). These include two families of serine/threonine ki- Cdc42) regulates a variety of important cell signaling and nases. The Rho kinase (ROK) and other ROK family kinases (13, T growth control pathways (1–3). In response to extracel- 14) are required for RhoA-mediated cell transformation, SRF ac- lular stimulation, activated Rho GTPases are involved in actin cy- tivation (15), and actin stress fiber formation. Protein kinase N and toskeletal reorganization (4–6), activation of transcription factors its related kinases also interact with GTP-RhoA, but their effector http://www.jimmunol.org/ such as serum response factor (SRF)3 (7) or NF-␬B (8), and cell functions are not clear (16). In addition, several adaptor proteins cycle progression (9, 10). The molecular mechanisms of the pleo- preferentially bind GTP-RhoA. They include rhophilin (17), rho- tropic effects of Rho GTPases are not clear and may reflect the tekin (18), kinectin (19), and citron (20). The specific functions of complex nature of Rho GTPase regulation (3). Like other members the adaptor effectors are not clear. Using RhoA effector domain of the Ras superfamily GTPases, Rho GTPases bind and hydrolyze mutants, it has recently been reported that distinct effectors are GTP, cycling between a biologically active GTP-bound and an involved in RhoA-mediated transformation of NIH3T3 cells, SRF inactive GDP-bound form. GTPase-activating proteins (GAPs) in- activation, and actin stress fiber formation (21, 22). crease the low intrinsic rate of GTP hydrolysis of Rho proteins, In T cells, Rho GTPases have been implicated in T cell devel- by guest on September 24, 2021 thus converting them to the inactive configuration (inhibitors). The opment and T cell activation (23). Rac1 has been implicated in guanine nucleotide dissociation inhibitors bind to Rho proteins and mediating signals from both TCR and costimulatory receptor lock them into their existing nucleotide-bound state, thus acting as CD28 during T cell activation (24). Cdc42 is reported to organize both positive and negative regulators of Rho proteins. A third class actin polarization of T cells toward APC (25), and defects in its of regulatory proteins, guanine nucleotide exchange factors (GEFs; signaling lead to T cell unresponsiveness (26). RhoA has recently also called Dbl family proteins; Refs. 3 and 11), stimulate the been implicated in mediating CD3/CD28 signals to promote IL-2 exchange of GDP for GTP on Rho proteins, thus converting them production (27). Recently, the RhoA GTPase has been shown to into the biologically active forms (activators). promote survival of pro- and early pre-thymocytes and cell cycle In addition, the diverse functions of RhoA are mediated by the progression of late pre-thymocytes (28). association of GTP-bound RhoA with a number of RhoA effector HIV-1 replication is modulated by a number of cellular signal- ing pathways regulated by both host and viral factors (29). For example, T cell activation is required for efficient HIV-1 replica- tion in resting T cells (30, 31). Activation of transcription factors Departments of *Microbiology and Immunology and †Pharmacology, ‡Lineberger Comprehensive Cancer Center, School of Medicine, and §Department of Epidemiol- such as NF-␬B (32) and NF-ATc (33, 34) leads to enhanced HIV ogy, School of Public Health, University of North Carolina, Chapel Hill, NC 27599; gene expression and replication. Although the Rho GTPases have ¶ and Onyx Pharmaceuticals, Richmond, CA 94806 been implicated in T cell activation (23, 28, 35), little is known Received for publication October 19, 1999. Accepted for publication March 6, 2000. about how Rho GTPases affect HIV-1 replication. The transmem- The costs of publication of this article were defrayed in part by the payment of page brane glycoprotein (TM or gp41) of HIV-1 contains a long cyto- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. plasmic domain (gp41C). Its function is not clear but has been 1 This work was supported in part by a grant from the March of Dimes Basil implicated in regulating HIV-1 replication and cytopathogenicity O’Connor Scholar Award (to L.S.), and by National Institutes of Health Grants (36). We recently demonstrated that gp41C interacted with the AI41356 (to L.S.) and CA63071 (to C.J.D.). C-terminal domain of p115-RhoGEF (37), which is a specific GEF 2 Address correspondence and reprint requests to Dr. Lishan Su, Department of Mi- and activator of the RhoA GTPase (38). We report here that both crobiology and Immunology, 22-048 Lineberger Comprehensive Cancer Center, CB 7295, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599. E-mail p115-RhoGEF and its specific activator, G␣13, can inhibit HIV-1 address: [email protected] replication. RhoA activation is required for the inhibition of HIV-1 3 Abbreviations used in this paper: SRF, serum response factor; GEF, guanine nu- replication. The RhoA effector activity involved is genetically sep- cleotide exchange factor; RT, reverse transcriptase; ROK, Rho kinase; GPCR, G protein-coupled receptor; GAP, GTPase-activating protein; WT, wild type; CA, con- arable from those involved in transformation of NIH3T3 cells, stitutively active; DH, Dbl homology; PH, pleckstrin homology. activation of SRF, and actin stress fiber formation. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 5370 RhoA-MEDIATED SUPPRESSION OF HIV-1 REPLICATION Materials and Methods Reagents, plasmids, and cell lines All p115-RhoGEF derivatives, including p115FL (1-912), p115dN (249- 912), p115dC (249-802), p115dDH (p115 with an internal deletion from 466 to 547, deleting the Dbl homology (DH) domain), p115dPH (1-720, deleting the C terminus and the pleckstrin homology (PH) domain), p115RGS (1-466, deleting both DH and PH domains), were cloned into the pcDNA3 mammalian expression vector as reported (38). The RhoA alleles (wild type (WT), the constitutively active (CA) 63L mutant and its effector domain mutants, and the dominant negative 19N mutant), lacZ, and CA mutant Cdc42 cDNAs were cloned in the pAX142 mammalian expression vector (39). The pNL4-3 plasmid encodes the entire HIV-1 genome DNA in pUC18 (40). The pNL4.Luc.RϪEϪ plasmid was obtained from the Na- tional Institutes of Health (NIH) AIDS Research and Reference Reagent Program (41). Human CD4 cDNA (T4-pMV7; Ref. 42) was also obtained from NIH. The RhoA (63L) effector domain mutants were constructed by site-directed mutagenesis of the RhoA63L gene and all were subcloned in the pcDNA3 vector. 293T and HeLa-MAGI cells (NIH AIDS Research and Reference Re- agent Program; Ref. 43) were maintained in DMEM supplemented with 10% FBS. Jurkat T cells (kindly provided by G. Crabtree, Stanford, CA) were maintained in RPMI 1640 supplemented with 10% FBS. Downloaded from HIV-1 production and replication in transfected human cells Transient production of HIV-1 was performed by transfecting the HIV-1 provirus NL4-3 (1 ␮g) with pcDNA3 vector (1 ␮g) or p115, G␣13, and RhoA derivatives (1 ␮g) and pAX142-lacZ (0.1 ␮g) in 293T cells in 6-well ␮ plates with LipofectAMINE (or 0.5 g each with Effectene; Qiagen, Santa http://www.jimmunol.org/ Clarita, CA). At 40–50 h after transfection, HIV-1 virions in the culture supernatant were measured by RT or p24 assays (44) and infectious units were determined by titering the supernatant on HeLa-CD4-LTR-lacZ cells (MAGI) as described previously (43).
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