Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3
Authors
Deng, PanUma Naresh, Nandhitha
Du, Yunguang
Lamech, Lilian T.
Yu, Jun
Zhu, Lihua Julie
Pukkila-Worley, Read
Haynes, Cole M.
UMass Chan Affiliations
Department of Molecular, Cell and Cancer BiologyDepartment of Medicine, Division of Infectious Diseases and Immunology
Document Type
Journal ArticlePublication Date
2019-03-26Keywords
mitochondrial UPRZIP-3
ATFS-1
UPRmt
immunity
Cell Biology
Immunology and Infectious Disease
Infectious Disease
Microbiology
Metadata
Show full item recordAbstract
Mitochondria generate most cellular energy and are targeted by multiple pathogens during infection. In turn, metazoans employ surveillance mechanisms such as the mitochondrial unfolded protein response (UPR(mt)) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPR(mt) is an adaptive transcriptional program regulated by the transcription factor ATFS-1, which induces genes that promote mitochondrial recovery and innate immunity. The bacterial pathogen Pseudomonas aeruginosa produces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPR(mt) activation. Here, we demonstrate that Pseudomonas aeruginosa exploits an intrinsic negative regulatory mechanism mediated by the Caenorhabditis elegans bZIP protein ZIP-3 to repress UPR(mt) activation. Strikingly, worms lacking zip-3 were impervious to Pseudomonas aeruginosa-mediated UPR(mt) repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPR(mt) activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, Pseudomonas aeruginosa unable to produce phenazines and thus elicit UPR(mt) activation were hypertoxic in zip-3-deletion worms. These data emphasize the significance of virulence-mediated UPR(mt) repression and the potency of the UPR(mt) as an antibacterial response.Source
Deng P, Uma Naresh N, Du Y, Lamech LT, Yu J, Zhu LJ, Pukkila-Worley R, Haynes CM. Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3. Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6146-6151. doi: 10.1073/pnas.1817259116. Epub 2019 Mar 8. PMID: 30850535; PMCID: PMC6442607. Link to article on publisher's site
DOI
10.1073/pnas.1817259116Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35189PubMed ID
30850535Related Resources
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1817259116