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

doi:10.1016/j.molcel.2012.12.004

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

Mol Cell. 2013 Feb 21;49(4):668-79. doi: 10.1016/j.molcel.2012.12.004. Epub 2013 Jan 11.

Authors

Jung-Hyun Lee¹, 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

Affiliation

¹ Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, 91054 Erlangen, Germany.

PMID: 23317503
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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / blood
ADAM Proteins / metabolism*
ADAM10 Protein
ADAM17 Protein
Adaptor Proteins, Signal Transducing / metabolism
Amino Acid Substitution
Amyloid Precursor Protein Secretases / blood
Amyloid Precursor Protein Secretases / metabolism*
Case-Control Studies
Enzyme Activation
HEK293 Cells
HIV Infections / blood
HIV Infections / enzymology
Heterogeneous-Nuclear Ribonucleoprotein K
Humans
Melanoma / blood
Melanoma / enzymology
Membrane Microdomains / enzymology
Membrane Proteins / blood
Membrane Proteins / metabolism*
Mutagenesis, Site-Directed
Paxillin / genetics
Paxillin / metabolism
Paxillin / physiology*
Phosphorylation
Polycomb Repressive Complex 2 / metabolism
Protein Binding
Protein Kinase C-delta / metabolism
Protein Precursors / metabolism
Protein Processing, Post-Translational
Protein Transport
Ribonucleoproteins / metabolism
Secretory Vesicles / metabolism
Signal Transduction
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
nef Gene Products, Human Immunodeficiency Virus / metabolism
nef Gene Products, Human Immunodeficiency Virus / physiology*
p21-Activated Kinases / metabolism
p21-Activated Kinases / physiology*

Substances

Adaptor Proteins, Signal Transducing
EED protein, human
Heterogeneous-Nuclear Ribonucleoprotein K
Membrane Proteins
PXN protein, human
Paxillin
Protein Precursors
Ribonucleoproteins
Tumor Necrosis Factor-alpha
nef Gene Products, Human Immunodeficiency Virus
nef protein, Human immunodeficiency virus 1
HNRNPK protein, human
Polycomb Repressive Complex 2
PAK1 protein, human
PAK2 protein, human
p21-Activated Kinases
Protein Kinase C-delta
Amyloid Precursor Protein Secretases
ADAM Proteins
ADAM10 Protein
ADAM10 protein, human
ADAM17 Protein
ADAM17 protein, human