TY - JOUR
T1 - Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones
AU - Rayo, Josep
AU - Gregor, Rachel
AU - Jacob, Nicholas T.
AU - Dandela, Rambabu
AU - Dubinsky, Luba
AU - Yashkin, Alex
AU - Aranovich, Alexander
AU - Thangaraj, Manikandan
AU - Ernst, Orna
AU - Barash, Eran
AU - Malitsky, Sergey
AU - Florea, Bogdan I.
AU - Krom, Bastiaan P.
AU - Wiemer, Erik A.C.
AU - Kickhoefer, Valerie A.
AU - Rome, Leonard H.
AU - Mathison, John C.
AU - Kaufmann, Gunnar F.
AU - Overkleeft, Herman S.
AU - Cravatt, Benjamin F.
AU - Zor, Tsaffrir
AU - Janda, Kim D.
AU - Ulevitch, Richard J.
AU - Kravchenko, Vladimir V.
AU - Meijler, Michael M.
N1 - ACKNOWLEDGMENTS. We thank Jiahuai Han for providing comments on the manuscript. We also thank Mark Karpasas for guidance on the proteomics analysis. The research was supported by grants from the European Research Council (Starting Grant #240356) to M.M.M. and the US–Israel Binational Science Foundation (Grant #2011360) to M.M.M. and B.F.C. R.G. is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/3/23
Y1 - 2021/3/23
N2 - The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa. Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).
AB - The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa. Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).
UR - http://www.scopus.com/inward/record.url?scp=85102691205&partnerID=8YFLogxK
U2 - 10.1073/pnas.2012529118
DO - 10.1073/pnas.2012529118
M3 - Article
C2 - 33723037
AN - SCOPUS:85102691205
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
M1 - e2012529118
ER -
