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J. Biol. Chem., Vol. 283, Issue 13, 8173-8182, March 28, 2008

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HIV-1 Nef Disrupts the Podocyte Actin Cytoskeleton by Interacting with Diaphanous Interacting Protein^*

Ting-chi Lu¹², John Cijiang He¹³, Zhao-hui Wang^¶, Xiaobei Feng^¶, Tomoko Fukumi-Tominaga^||, Nan Chen^¶, Jin Xu, Ravi Iyengar^**, and Paul E. Klotman

From the Departments of Medicine and ^**Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, the James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468, the ^¶Department of Nephrology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and the ^||Section of Cell Signaling, National Institute of Physiological Science, Okazaki 444-8585, Japan

The ability of the human immunodeficiency virus, type 1 (HIV-1) protein Nef to induce cytoskeleton changes in infected host cells is a key event in viral replication. In renal podocytes, we found that Nef induced loss of stress fibers and increased lamellipodia, pathological changes leading to proteinuria in HIV-associated nephropathy. These morphological changes were mediated by Nef-induced Rac1 activation and RhoA inhibition. We identified a new interaction between Nef and diaphanous interacting protein (DIP), a recently described regulator of Rho and Rac signaling. We found that the Src homology 3 binding domain of DIP and the Nef PXXP motif were required for this interaction. Nef also interacts with Vav2 in podocytes. DIP and Vav2 both interact directly with Nef in a competitive manner. DIP interacts with p190RhoGAP, and intact DIP was required for Nef-induced phosphorylation of p190RhoGAP. DIP also interacts with Vav2, and although DIP enhanced baseline phosphorylation of Vav2, it was not required for Nef-induced Vav2 activation. In Nef-infected podocytes, Src kinase induces phosphorylation of DIP, p190RhoGAP, and Vav2, leading to RhoA inhibition and Rac1 activation. Inhibition of the Nef-induced signaling pathway by using a dominant negative of either Src or DIP or siRNA for DIP or p190RhoAGAP restored RhoA activity and stress fiber formation in Nef-infected podocytes, whereas siRNA for Vav2 reduced Rac1 activity and formation of lamellipodia. We conclude that in HIV-infected podocytes, Nef, through the recruitment of DIP and p190RhoAGAP to Nef-Src complex, activates p190RhoAGAP and down-regulates RhoA activity.

Received for publication, October 30, 2007 , and in revised form, January 30, 2008.

^* This work was supported in part by National Institutes of Health (NIH) Grants P01 DK056492 (to P. K.) and R01 GM54508 (to R. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of NIH Research Fellowship Award K08 DK079781.

³ Recipient of an NIH Career Development Award K08 DK065495 and supported by NIH Grant R01 DK078897. To whom correspondence should be addressed: Box 1243, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029. Tel.: 212-241-8004; Fax: 212-987-0389; E-mail: Cijiang.he{at}mssm.edu.

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