HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases

Jung Hyun Lee, Sebastian Wittki, Tanja Bräu, Florian S. Dreyer, Kirsten Krätzel, Jochen Dindorf, Ian C.D. Johnston, Stefanie Gross, Elisabeth Kremmer, Reinhard Zeidler, Ursula Schlötzer-Schrehardt, Mathias Lichtenheld, Kalle Saksela, Thomas Harrer, Gerold Schuler, Maurizio Federico, Andreas S. Baur

Research output: Contribution to journalArticle

56 Scopus citations

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 TNFα converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNFα and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNFα. 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.

Original languageEnglish (US)
Pages (from-to)668-679
Number of pages12
JournalMolecular Cell
Volume49
Issue number4
DOIs
StatePublished - Feb 21 2013

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Lee, J. H., Wittki, S., Bräu, T., Dreyer, F. S., Krätzel, K., Dindorf, J., Johnston, I. C. D., Gross, S., Kremmer, E., Zeidler, R., Schlötzer-Schrehardt, U., Lichtenheld, M., Saksela, K., Harrer, T., Schuler, G., Federico, M., & Baur, A. S. (2013). HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases. Molecular Cell, 49(4), 668-679. https://doi.org/10.1016/j.molcel.2012.12.004