Hos, Nina Judith, Ganesan, Raja, Gutierrez, Saray, Hos, Deniz, Klimek, Jennifer, Abdullah, Zeinab, Kroenke, Martin and Robinson, Nirmal ORCID: 0000-0002-7361-9491 (2017). Type I interferon enhances necroptosis of Salmonella Typhimurium-infected macrophages by impairing antioxidative stress responses. J. Cell Biol., 216 (12). S. 4107 - 4122. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-8140

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Abstract

Salmonella enterica serovar Typhimurium exploits the host's type I interferon (IFN-I) response to induce receptor-interacting protein (RIP) kinase-mediated necroptosis in macrophages. However, the events that drive necroptosis execution downstream of IFN-I and RIP signaling remain elusive. In this study, we demonstrate that S. Typhimurium infection causes IFN-I-mediated up-regulation of the mitochondrial phosphatase Pgam5 through RIP3. Pgam5 subsequently interacts with Nrf2, which sequesters Nrf2 in the cytosol, thereby repressing the transcription of Nrf2-dependent antioxidative genes. The impaired ability to respond to S. Typhimurium-induced oxidative stress results in reactive oxygen species-mediated mitochondrial damage, energy depletion, transient induction of autophagy, and autophagic degradation of p62. Reduced p62 levels impair interaction of p62 with Keap1, which further decreases Nrf2 function and antioxidative responses to S. Typhimurium infection, eventually leading to cell death. Collectively, we identify impaired Nrf2-dependent redox homeostasis as an important mechanism that promotes cell death downstream of IFN-I and RIP3 signaling in S. Typhimurium-infected macrophages.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hos, Nina JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ganesan, RajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutierrez, SarayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hos, DenizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klimek, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdullah, ZeinabUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, NirmalUNSPECIFIEDorcid.org/0000-0002-7361-9491UNSPECIFIED
URN: urn:nbn:de:hbz:38-209476
DOI: 10.1083/jcb.201701107
Journal or Publication Title: J. Cell Biol.
Volume: 216
Number: 12
Page Range: S. 4107 - 4122
Date: 2017
Publisher: ROCKEFELLER UNIV PRESS
Place of Publication: NEW YORK
ISSN: 1540-8140
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INTRACELLULAR HYALINE BODIES; UBIQUITIN LIGASE COMPLEX; CELL-DEATH; SELECTIVE AUTOPHAGY; OXIDATIVE STRESS; MALLORY BODIES; P62; NRF2; ACTIVATION; PROTEINMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20947

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