RRC ID |
59415
|
著者 |
Tillman EJ, Richardson CE, Cattie DJ, Reddy KC, Lehrbach NJ, Droste R, Ruvkun G, Kim DH.
|
タイトル |
Endoplasmic Reticulum Homeostasis Is Modulated by the Forkhead Transcription Factor FKH-9 During Infection of Caenorhabditis elegans.
|
ジャーナル |
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.
|
巻・号 |
210(4)
|
ページ |
1329-1337
|
公開日 |
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
|
引用数 |
3
|
リソース情報 |
線虫 |
tm2482 |