The Mediator subunit MDT-15 confers metabolic adaptation to ingested material.
In eukaryotes, RNA polymerase II (Pol(II)) dependent gene expression requires accessory factors termed transcriptional coregulators. One coregulator that universally contributes to Pol(II)-dependent transcription is the Mediator, a multisubunit complex that is targeted by many transcriptional regulatory factors. For example, the Caenorhabditis elegans Mediator subunit MDT-15 confers the regulatory actions of the sterol response element binding protein SBP-1 and the nuclear hormone receptor NHR-49 on fatty acid metabolism. Here, we demonstrate that MDT-15 displays a broader spectrum of activities, and that it integrates metabolic responses to materials ingested by C. elegans. Depletion of MDT-15 protein or mutation of the mdt-15 gene abrogated induction of specific detoxification genes in response to certain xenobiotics or heavy metals, rendering these animals hypersensitive to toxin exposure. Intriguingly, MDT-15 appeared to selectively affect stress responses related to ingestion, as MDT-15 functional defects did not abrogate other stress responses, e.g., thermotolerance. Together with our previous finding that MDT-15:NHR-49 regulatory complexes coordinate a sector of the fasting response, we propose a model whereby MDT-15 integrates several transcriptional regulatory pathways to monitor both the availability and quality of ingested materials, including nutrients and xenobiotic compounds.
Taubert
Stefan
S
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
Hansen
Malene
M
Van Gilst
Marc R
MR
Cooper
Samantha B
SB
Yamamoto
Keith R
KR
D000222:Adaptation, Physiological; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005502:Food; D020869:Gene Expression Profiling; D017238:Genes, Helminth; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D008658:Inactivation, Metabolic; D050356:Lipid Metabolism; D019216:Metals, Heavy / Q000378:metabolism / Q000633:toxicity; D008954:Models, Biological; D009154:Mutation; D021122:Protein Subunits; D034622:RNA Interference; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity
D029742:Caenorhabditis elegans Proteins; D019216:Metals, Heavy; D021122:Protein Subunits; D015534:Trans-Activators; D015262:Xenobiotics