Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones

Josep Rayo, Rachel Gregor, Nicholas T. Jacob, Rambabu Dandela, Luba Dubinsky, Alex Yashkin, Alexander Aranovich, Manikandan Thangaraj, Orna Ernst, Eran Barash, Sergey Malitsky, Bogdan I. Florea, Bastiaan P. Krom, Erik A.C. Wiemer, Valerie A. Kickhoefer, Leonard H. Rome, John C. Mathison, Gunnar F. Kaufmann, Herman S. Overkleeft, Benjamin F. CravattTsaffrir Zor, Kim D. Janda, Richard J. Ulevitch, Vladimir V. Kravchenko*, Michael M. Meijler

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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).

Original languageEnglish
Article numbere2012529118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
Publication statusPublished - 23 Mar 2021

Bibliographical note

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.

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