Reference : Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1α ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/47965
Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1α kinase inhibitor KIRA6 through HSP60 targeting
English
Rufo, Nicole [Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium > > > ; VIB Center for Cancer Biology Research, Leuven, Belgium.]
Korovesis, Dimitris [Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium]
Van Eygen, Sofie [Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. > > > ; VIB Center for Cancer Biology Research, Leuven, Belgium.]
Derua, Rita [Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine and SyBioMa, KU Leuven, Leuven, Belgium]
Garg, Abhishek D. [Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.]
Finotello, Francesca [Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria]
Vara-Perez, Monica [Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium > > > ; VIB Center for Cancer Biology Research, Leuven, Belgium]
Rožanc, Jan [Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg > > > ; ProtATonce Ltd, Science Park Demokritos, Athens, Greece]
Dewaele, Michael [VIB Center for Cancer Biology Research, Leuven, Belgium > > > ; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium]
de Witte, Peter A. [Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium]
Alexopoulos, Leonidas G. [ProtATonce Ltd, Science Park Demokritos, Athens, Greece > > > ; BioSys Lab, Department of Mechanical Engineering, National Technical University of Athens, Zografou, Greece]
Janssens, Sophie [Laboratory for ER stress and Inflammation, VIB Center for Inflammation Research and Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.]
Sinkkonen, Lasse mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Sauter, Thomas mailto [University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) >]
Verhelst, Steven H. L. [Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. > > > ; AG Chemical Proteomics, Leibniz Institute for Analytical Sciences ISAS, e.V., Dortmund, Germany.]
Agostinis, Patrizia [Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. > > > ; VIB Center for Cancer Biology Research, Leuven, Belgium]
27-Aug-2021
Cell Death and Differentiation
Nature Publishing Group
Yes (verified by ORBilu)
International
1350-9047
1476-5403
London
United Kingdom
[en] Mounting evidence indicates that immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress favor proficient cancer cell-immune interactions, by stimulating the release of immunomodulatory/ proinflammatory factors by stressed or dying cancer cells. UPR-driven transcription of proinflammatory cytokines/chemokines exert beneficial or detrimental effects on tumor growth and antitumor immunity, but the cell-autonomous machinery governing the cancer cell inflammatory output in response to immunogenic therapies remains poorly defined. Here, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated a NF-κB/AP-1-inflammatory stress response, which dissociated from both cell death and UPR. This stress-induced inflammation was specifically abolished by the IRE1α-kinase inhibitor KIRA6. Supernatants from immunogenic chemotherapy and KIRA6 co-treated cancer cells were deprived of proinflammatory/chemoattractant factors and failed to mobilize neutrophils and induce dendritic cell maturation. Furthermore, KIRA6 significantly reduced the in vivo vaccination potential of dying cancer cells responding to immunogenic chemotherapy. Mechanistically, we found that the anti-inflammatory effect of KIRA6 was still effective in IRE1α-deficient cells, indicating a hitherto unknown off-target effector of this IRE1α-kinase inhibitor. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry, and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the IKK-driven NF-κB pathway. In sum, our study unravels that HSP60 is a KIRA6-inhibitable upstream regulator of the NF-κB/AP-1-inflammatory stress responses evoked by immunogenic treatments. It also urges caution when interpreting the anti-inflammatory action of IRE1α chemical inhibitors.
Researchers
http://hdl.handle.net/10993/47965
10.1038/s41418-021-00853-5

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