HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases

Lee JH, Wittki S, Braeu T, Dreyer F, Kraetzel K, Dindorf J, Johnston ICD, Gross S, Kremmer E, Zeidler R, Schlötzer-Schrehardt U, Lichtenheld M, Saksela K, Harrer T, Schuler G, Federico M, Baur A (2013)

Publication Type: Journal article

Publication year: 2013

Journal

Molecular Cell Elsevier (Cell Press)

Book Volume: 49

Pages Range: 668-79

Journal Issue: 4

DOI: 10.1016/j.molcel.2012.12.004

Abstract

The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin effector paxillin to recruit and activate TNF? converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNF? and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNF?. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment.

Authors with CRIS profile

Florian Dreyer Department of Dermatology Ursula Schlötzer-Schrehardt Medizinische Fakultät Thomas Harrer Professur für Innere Medizin mit dem Schwerpunkt Immundefizienz Gerold Schuler Lehrstuhl für Haut- und Geschlechtskrankheiten

Additional Organisation(s)

Department of Ophthalmology

Involved external institutions

Helsingin yliopisto / University of Helsinki FI Finland (FI) University of Miami US United States (USA) (US) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Italian National Health Institute / Istituto Superiore di Sanità (ISS) IT Italy (IT) Miltenyi Biotec GmbH DE Germany (DE)

How to cite

APA:

Lee, J.-H., Wittki, S., Braeu, T., Dreyer, F., Kraetzel, K., Dindorf, J.,... Baur, A. (2013). HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Molecular Cell, 49(4), 668-79. https://dx.doi.org/10.1016/j.molcel.2012.12.004

MLA:

Lee, Jung-Hyun, et al. "HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases." Molecular Cell 49.4 (2013): 668-79.

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