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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.<\/jats:p>","DOI":"10.1534\/genetics.118.301450","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T21:49:34Z","timestamp":1538689774000},"page":"1329-1337","source":"Crossref","is-referenced-by-count":20,"title":["Endoplasmic Reticulum Homeostasis Is Modulated by the Forkhead Transcription Factor FKH-9 During Infection of <i>Caenorhabditis elegans<\/i>"],"prefix":"10.1093","volume":"210","author":[{"given":"Erik J","family":"Tillman","sequence":"first","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J","family":"Cattie","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirthi C","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas J","family":"Lehrbach","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Droste","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"},{"name":"Howard Hughes Medical Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Ruvkun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis H","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,10,15]]},"reference":[{"key":"2022011706424224800_bib1","doi-asserted-by":"publisher","first-page":"10388","DOI":"10.1038\/ncomms10388","article-title":"Axotomy-induced HIF-serotonin signalling axis promotes axon regeneration in C. elegans.","volume":"7","author":"Alam","year":"2016","journal-title":"Nat. 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