An Intracellular Pathogen Response Pathway Promotes Proteostasis in C. elegans

Kirthi C. Reddy, Tal Dror, Jessica N. Sowa, Johan Panek, Kevin Chen, Efrem S. Lim, David Wang, Emily R. Troemel

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Maintenance of protein homeostasis, or proteostasis, is crucial for organismal health. Disruption of proteostasis can lead to the accumulation of protein aggregates, which are associated with aging and many human diseases such as Alzheimer's disease [1–3]. Through analysis of the C. elegans host response to intracellular infection, we describe here a novel response pathway that enhances proteostasis capacity and appears to act in parallel to well-studied proteostasis pathways. These findings are based on analysis of the transcriptional response to infection by the intracellular pathogen Nematocida parisii [4]. The response to N. parisii is strikingly similar to the response to infection by the Orsay virus, another natural intracellular pathogen of C. elegans, and is distinct from responses to extracellular pathogen infection [4–6]. We have therefore named this common transcriptional response the intracellular pathogen response (IPR), and it includes upregulation of several predicted ubiquitin ligase complex components such as the cullin cul-6. Through a forward genetic screen we found pals-22, a gene of previously unknown function, to be a repressor of the cul-6/cullin gene and other IPR gene expression. Interestingly, pals-22 mutants have increased thermotolerance and reduced levels of stress-induced polyglutamine aggregates, likely due to upregulated IPR gene expression. We found the enhanced stress resistance of pals-22 mutants to be dependent on cul-6, suggesting that pals-22 mutants have increased activity of a CUL-6/cullin-containing ubiquitin ligase complex. pals-22 mutant phenotypes appear independent of the well-studied heat shock and insulin signaling pathways, indicating that the IPR is a distinct pathway that protects animals from proteotoxic stress. Reddy et al. report a pathway in C. elegans called the intracellular pathogen response, or IPR, which appears to be independent of known stress response pathways. They identify PALS-22 as a negative regulator of the IPR, with pals-22 mutants showing increased resistance to proteotoxic stress dependent on the ubiquitin ligase component CUL-6.

Original languageEnglish (US)
Pages (from-to)3544-3553.e5
JournalCurrent Biology
Volume27
Issue number22
DOIs
StatePublished - Nov 20 2017

Keywords

  • C. elegans
  • cul-6
  • host response
  • intracellular pathogen response
  • microsporidia
  • pals-22
  • polyQ aggregates
  • proteostasis
  • thermotolerance
  • virus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Reddy, K. C., Dror, T., Sowa, J. N., Panek, J., Chen, K., Lim, E. S., Wang, D., & Troemel, E. R. (2017). An Intracellular Pathogen Response Pathway Promotes Proteostasis in C. elegans. Current Biology, 27(22), 3544-3553.e5. https://doi.org/10.1016/j.cub.2017.10.009