Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis

Version 1 : Received: 16 March 2022 / Approved: 18 March 2022 / Online: 18 March 2022 (09:21:45 CET)

A peer-reviewed article of this Preprint also exists.

Walker, A.C.; Bhargava, R.; Dove, A.S.; Brust, A.S.; Owji, A.A.; Czyż, D.M. Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis. Int. J. Mol. Sci. 2022, 23, 4807. Walker, A.C.; Bhargava, R.; Dove, A.S.; Brust, A.S.; Owji, A.A.; Czyż, D.M. Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis. Int. J. Mol. Sci. 2022, 23, 4807.

Journal reference: Int. J. Mol. Sci. 2022, 23, 4807
DOI: 10.3390/ijms23094807

Abstract

Neurodegenerative protein conformational diseases are characterized by misfolding and aggregation of metastable proteins encoded within the host genome. The host is also home to thousands of proteins encoded within exogenous genomes harbored by bacteria, fungi, and viruses. Yet, their contributions to host protein-folding homeostasis, or proteostasis, remain elusive. Recent studies, including our previous work, suggest that bacterial products contribute to toxic aggregation of endogenous host proteins. We refer to these products as bacteria-derived protein aggregates (BDPAs). Furthermore, antibiotics were recently associated with increased risk for neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis  possibly by virtue of altering the composition of the human gut microbiota. Other studies have shown a negative correlation between disease progression and antibiotic administration, supporting their protective effect against neurodegenerative diseases. These contradicting studies emphasize the complexity of the human gut microbiota, the gut-brain axis, and the effect of antibiotics. Here, we further our understanding of bacteria’s effect on host protein folding using the model Caenorhabditis elegans. We employed genetic and chemical methods to demonstrate that the proteotoxic effect of bacteria on host protein folding correlates with the presence of BDPAs. Furthermore, the abundance and proteotoxicity of BDPAs are influenced by gentamicin, an aminoglycoside antibiotic that induces protein misfolding, and by butyrate, a short-chain fatty acid that we previously found to affect host protein aggregation and the associated toxicity. Collectively, these results increase our understanding of host-bacteria interactions in the context of protein conformational diseases.

Keywords

Caenorhabditis elegans; proteostasis; bacteria; neurodegenerative diseases; protein aggregates; protein conformational disease; butyrate; aminoglycoside; Pseudomonas aeruginosa

Subject

LIFE SCIENCES, Microbiology

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