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Filamin-A regulates actin-dependent clustering of HIV receptors

Nature Cell Biology volume 9, pages 838–846 (2007)Cite this article

Abstract

Human immunodeficiency virus (HIV)-1 infection requires envelope (Env) glycoprotein gp120-induced clustering of CD4 and coreceptors (CCR5 or CXCR4) on the cell surface; this enables Env gp41 activation and formation of a complex that mediates fusion between Env-containing and target-cell membranes1. Kinetic studies show that viral receptors are actively transported to the Env-receptor interface in a process that depends on plasma membrane composition and the actin cytoskeleton2,3,4,5,6,7. The mechanisms by which HIV-1 induces F-actin rearrangement in the target cell remain largely unknown. Here, we show that CD4 and the coreceptors interact with the actin-binding protein filamin-A, whose binding to HIV-1 receptors regulates their clustering on the cell surface. We found that gp120 binding to cell receptors induces transient cofilin-phosphorylation inactivation through a RhoA–ROCK-dependent mechanism. Blockade of filamin-A interaction with CD4 and/or coreceptors inhibits gp120-induced RhoA activation and cofilin inactivation. Our results thus identify filamin-A as an adaptor protein that links HIV-1 receptors to the actin cytoskeleton remodelling machinery, which may facilitate virus infection.

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Figure 1: Identification of filamin-A as a CD4-binding protein.
Figure 2: Identification of residues involved in the filamin-A–CD4 interaction.
Figure 3: Filamin-A interaction with CXCR4 and CCR5.
Figure 4: Filamin-A involvement in HIV-1 receptor clustering and cell infection.
Figure 5: Filamin-A involvement in gp120-induced signalling.

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Protein Data Bank

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Acknowledgements

We thank T. Stossel, D. Rodríguez, A. C. Carrera, F. Sánchez-Madrid and M. A. del Pozo for reagents and discussion, M. Martín and L. Kremer (CNB Protein Tools Unit) for BIAcore analysis, M. C. Moreno-Ortiz for cell sorting, C. M. Martínez-Garcia for technical help, and C. Mark for editorial assistance. This work was supported in part by the Spanish Ministry of Education and Science (SAF2005-00241) and the Intramural CSIC Program (PIF 20050F0212) to S.M., the European Union FP6 (INNOCHEM, LSHB-CT-2005-518167) to S.M. and C.M.A., the Instituto de Salud Carlos III (FIS030300; G030173) to R.D., and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to D.S.D. A.R. is a recipient of MIRG-CT-2005-016499. The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (CSIC) and by Pfizer.

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  1. Ana Rojas & Alfonso Valencia

    Present address: Current address: Computational and Structural Biology Group, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain.,

Authors and Affiliations

  1. Department of Immunology and Oncology Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Darwin 3, Campus de Cantoblanco, Madrid, 28049, Spain

    Sonia Jiménez-Baranda, Concepción Gómez-Moutón, Emilia Mira, Rosa Ana Lacalle, Carlos Martínez-A. & Santos Mañes

  2. Bioinformatics Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Darwin 3, Campus de Cantoblanco, Madrid, 28049, Spain

    Ana Rojas & Alfonso Valencia

  3. Servicio de Microbiología, Hospital 12 de Octubre, Avda. de Córdoba, Madrid, 28041, Spain

    Lorena Martínez-Prats & Rafael Delgado

  4. CCR Nanobiology Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, 21702-1201, MD, USA

    Dimiter S. Dimitrov

  5. Venetian Institute of Molecular Medicine, University of Padova, Padua, 35100, Italy

    Antonella Viola

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Contributions

S.J.-B. designed and performed most experiments and prepared the figures. S.M. and R.A.L. obtained CD4 mutants. C.G.-M. performed functional assays and yeast two-hybrid analysis of CXCR4 and CCR5. A.R. and A. Valencia did the bioinformatic analysis. A. Viola designed the immunocavitation experiments and provided reagents. R.D. and L.M.-P designed and performed virus infection experiments. D.S.D. and C.M.-A. contributed to discussion and provided reagents. S.M. conceived the study, planned and coordinated experiments, and wrote the manuscript.

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Correspondence to Santos Mañes.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary figures S1, S2, S3, S4, S5 and Supplementary Methods (PDF 999 kb)

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Jiménez-Baranda, S., Gómez-Moutón, C., Rojas, A. et al. Filamin-A regulates actin-dependent clustering of HIV receptors. Nat Cell Biol 9, 838–846 (2007). https://doi.org/10.1038/ncb1610

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