RRC ID 59415
Author Tillman EJ, Richardson CE, Cattie DJ, Reddy KC, Lehrbach NJ, Droste R, Ruvkun G, Kim DH.
Title Endoplasmic Reticulum Homeostasis Is Modulated by the Forkhead Transcription Factor FKH-9 During Infection of Caenorhabditis elegans.
Journal Genetics
Abstract Animals have evolved critical mechanisms to maintain cellular and organismal proteostasis during development, disease, and exposure to environmental stressors. The Unfolded Protein Response (UPR) is a conserved pathway that senses and responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen. We have previously demonstrated that the IRE-1-XBP-1 branch of the UPR is required to maintain Caenorhabditis elegans ER homeostasis during larval development in the presence of pathogenic Pseudomonas aeruginosa In this study, we identify loss-of-function mutations in four conserved transcriptional regulators that suppress the larval lethality of xbp-1 mutant animals caused by immune activation in response to infection by pathogenic bacteria: FKH-9, a forkhead family transcription factor; ARID-1, an ARID/Bright domain-containing transcription factor; HCF-1, a transcriptional regulator that associates with histone modifying enzymes; and SIN-3, a subunit of a histone deacetylase complex. Further characterization of FKH-9 suggests that loss of FKH-9 enhances resistance to the ER toxin tunicamycin and results in enhanced ER-associated degradation (ERAD). Increased ERAD activity of fkh-9 loss-of-function mutants is accompanied by a diminished capacity to degrade cytosolic proteasomal substrates and a corresponding increased sensitivity to the proteasomal inhibitor bortezomib. Our data underscore how the balance between ER and cytosolic proteostasis can be influenced by compensatory activation of ERAD during the physiological ER stress of infection and immune activation.
Volume 210(4)
Pages 1329-1337
Published 2018-12-1
DOI 10.1534/genetics.118.301450
PII genetics.118.301450
PMID 30287474
PMC PMC6283152
MeSH Animals Bortezomib / administration & dosage Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / genetics* Carrier Proteins / genetics Endoplasmic Reticulum / genetics* Endoplasmic Reticulum / metabolism Endoplasmic Reticulum Stress / drug effects Endoplasmic Reticulum Stress / genetics Forkhead Transcription Factors / genetics* Gene Expression Regulation, Developmental / drug effects Homeostasis / genetics* Host Cell Factor C1 / genetics Immune System / growth & development Larva / genetics Larva / growth & development Mutation Protein Serine-Threonine Kinases / genetics Tunicamycin / toxicity Unfolded Protein Response / genetics*
IF 3.564
Times Cited 3
C.elegans tm2482