Abstract
Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal transduction of the mitochondrial unfolded protein response (UPR(mt)) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPR(mt), and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS-induced UPR(mt). Activation of the UPR(mt), but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS-induced UPR(mt), suggesting that surveillance-activated defenses specifically inhibit the UPR(mt) but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Caenorhabditis elegans Proteins* / genetics
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Caenorhabditis elegans Proteins* / metabolism
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Caenorhabditis elegans* / genetics
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Caenorhabditis elegans* / growth & development
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Caenorhabditis elegans* / metabolism
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Endoplasmic Reticulum / genetics
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Endoplasmic Reticulum / metabolism
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JNK Mitogen-Activated Protein Kinases* / genetics
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JNK Mitogen-Activated Protein Kinases* / metabolism
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Mitochondria* / drug effects
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Mitochondria* / metabolism
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Molecular Chaperones
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Paraquat / pharmacology
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Phosphorylation
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Protein Folding
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Reactive Oxygen Species* / metabolism
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Reactive Oxygen Species* / toxicity
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Signal Transduction / drug effects
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Transcription Factors / metabolism
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Unfolded Protein Response / drug effects
Substances
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ATFS-1 protein, C elegans
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ATP-Binding Cassette Transporters
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Caenorhabditis elegans Proteins
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HAF-1 protein, C elegans
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Molecular Chaperones
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Reactive Oxygen Species
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Transcription Factors
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JNK Mitogen-Activated Protein Kinases
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KGB-1 protein, C elegans
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Paraquat
Grants and funding
Some strains in this study were obtained from the Caenorhabditis Genetics Center (CGC), which is funded by the NIH National Centre for Research Resources (NCRR). This study was supported in part by the Excellence Initiative of the German Federal and State Governments (GSC 4, Spemann Graduate School and excellence cluster BIOSS) to EDR and RB, and by DFG SFB850 and SFB746 to RB. The article processing charge was funded by the German Research Foundation (DFG) and the Albert Ludwigs University Freiburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.