Abstract
Protein kinase activity must be precisely regulated, but how a cell governs hyperactive kinases remains unclear. In this study, we generated a constitutively active mitogen-activated protein kinase DYF-5 (DYF-5CA) in Caenorhabditis elegans that disrupted sensory cilia. Genetic suppressor screens identified that mutations of ADR-2, an RNA adenosine deaminase, rescued ciliary phenotypes of dyf-5CA We found that dyf-5CA animals abnormally transcribed antisense RNAs that pair with dyf-5CA messenger RNA (mRNA) to form double-stranded RNA, recruiting ADR-2 to edit the region ectopically. RNA editing impaired dyf-5CA mRNA splicing, and the resultant intron retentions blocked DYF-5CA protein translation and activated nonsense-mediated dyf-5CA mRNA decay. The kinase RNA editing requires kinase hyperactivity. The similar RNA editing-dependent feedback regulation restricted the other ciliary kinases NEKL-4/NEK10 and DYF-18/CCRK, which suggests a widespread mechanism that underlies kinase regulation.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Deaminase / genetics
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Adenosine Deaminase / metabolism
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Animals
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Caenorhabditis elegans / enzymology*
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / metabolism*
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Cell Nucleus / metabolism
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Cilia / enzymology
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Cilia / metabolism*
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Enzyme Activation
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Mitogen-Activated Protein Kinases / genetics*
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Mitogen-Activated Protein Kinases / metabolism*
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Phenotype
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / metabolism
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RNA Editing*
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RNA Precursors / genetics
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RNA Precursors / metabolism
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RNA Splicing
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RNA Stability
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RNA, Antisense / genetics
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RNA, Antisense / metabolism
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RNA, Double-Stranded / genetics
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RNA, Double-Stranded / metabolism
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RNA, Helminth / genetics
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RNA, Helminth / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction
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Transcription, Genetic
Substances
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Caenorhabditis elegans Proteins
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RNA Precursors
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RNA, Antisense
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RNA, Double-Stranded
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RNA, Helminth
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RNA, Messenger
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DYF-18 protein, C elegans
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Protein Serine-Threonine Kinases
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DYF-5 protein, C elegans
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Mitogen-Activated Protein Kinases
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Adenosine Deaminase
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Adr-2 protein, C elegans