Title

Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology; Department of Molecular, Cell and Cancer Biology

Publication Date

2019-03-26

Document Type

Article

Disciplines

Cell Biology | Immunology and Infectious Disease | Infectious Disease | Microbiology

Abstract

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.

Keywords

mitochondrial UPR, ZIP-3, ATFS-1, UPRmt, immunity

DOI of Published Version

10.1073/pnas.1817259116

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

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

30850535

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