Skn-1 Activation During Infection of Caenorhabditis elegans Requires CDC-48 and Endoplasmic Reticulum Proteostasis

Authors

Carolaing Gabaldón
Ozgur Karakuzu
Danielle A Garsin

Language

English

Publication Date

11-6-2024

Journal

Genetics

DOI

10.1093/genetics/iyae131

PMID

39166513

PMCID

PMC11538416

PubMedCentral® Posted Date

8-21-2024

PubMedCentral® Full Text Version

Post-print

Abstract

During challenge of Caenorhabditis elegans with human bacterial pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, the elicited host response can be damaging if not properly controlled. The activation of Nrf (nuclear factor erythroid-related factor)/CNC (Cap-n-collar) transcriptional regulators modulates the response by upregulating genes that neutralize damaging molecules and promote repair processes. Activation of the C. elegans Nrf ortholog, SKN-1, is tightly controlled by a myriad of regulatory mechanisms, but a central feature is an activating phosphorylation accomplished by the p38 mitogen-activated kinase (MAPK) cascade. In this work, loss of CDC-48, an AAA+ ATPase, was observed to severely compromise SKN-1 activation on pathogen and we sought to understand the mechanism. CDC-48 is part of the endoplasmic reticulum (ER)-associated degradation (ERAD) complex where it functions as a remodeling chaperone enabling the translocation of proteins from the ER to the cytoplasm for degradation by the proteosome. Interestingly, one of the proteins retrotranslocated by ERAD, a process necessary for its activation, is SKN-1A, the ER isoform of SKN-1. However, we discovered that SKN-1A is not activated by pathogen exposure in marked contrast to the cytoplasmic-associated isoform SKN-1C. Rather, loss of CDC-48 blocks the antioxidant response normally orchestrated by SKN-1C by strongly inducing the unfolded protein response (UPRER). The data are consistent with the model of these 2 pathways being mutually inhibitory and support the emerging paradigm in the field of coordinated cooperation between different stress responses.

Keywords

Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Transcription Factors, DNA-Binding Proteins, Valosin Containing Protein, Endoplasmic Reticulum, Proteostasis, Endoplasmic Reticulum-Associated Degradation, Pseudomonas aeruginosa, Enterococcus faecalis, Caenorhabditis elegans, CDC-48, SKN-1, Nrf, infection, stress response

Published Open-Access

yes

Recommended Citation

Carolaing Gabaldón, Ozgur Karakuzu, and Danielle A Garsin, "Skn-1 Activation During Infection of Caenorhabditis elegans Requires CDC-48 and Endoplasmic Reticulum Proteostasis" (2024). Faculty, Staff and Student Publications. 5726.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5726