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

J. Rayo, R. Gregor, N.T. Jacob, R. Dandela, L. Dubinsky, A. Yashkin, A. Aranovich, M. Thangaraj, O. Ernst, E. Barash, S. Malitsky, B.I. Florea, B.P. Krom, E.A.C. Wiemer, V.A. Kickhoefer, L.H. Rome, J.C. Mathison, G.F. Kaufmann, H.S. Overkleeft, B.F. CravattT. Zor, K.D. Janda, R.J. Ulevitch, V.V. Kravchenko, M.M. Meijler

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

© 2021 National Academy of Sciences. All rights reserved.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
Volume118
Issue number12
DOIs
Publication statusPublished - 23 Mar 2021

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