TY - JOUR
T1 - HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases
AU - Lee, Jung Hyun
AU - Wittki, Sebastian
AU - Bräu, Tanja
AU - Dreyer, Florian S.
AU - Krätzel, Kirsten
AU - Dindorf, Jochen
AU - Johnston, Ian C.D.
AU - Gross, Stefanie
AU - Kremmer, Elisabeth
AU - Zeidler, Reinhard
AU - Schlötzer-Schrehardt, Ursula
AU - Lichtenheld, Mathias
AU - Saksela, Kalle
AU - Harrer, Thomas
AU - Schuler, Gerold
AU - Federico, Maurizio
AU - Baur, Andreas S.
PY - 2013/2/21
Y1 - 2013/2/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84874238349&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.12.004
DO - 10.1016/j.molcel.2012.12.004
M3 - Article
C2 - 23317503
AN - SCOPUS:84874238349
SN - 1097-2765
VL - 49
SP - 668
EP - 679
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -
