Science: RNA editing restricts hyperactive ciliary kinases

dWeb.News Article from Li D. Liu Y. Yi P. Zhu Z. Li W. Zhang Q. C. Li J. B. Ou G. dWeb.News


RNA editing restricts ciliary kinases

Ciliary kinases are essential for cilia formation and function but it remains unknown how their activities are regulated in vivo. Li et al. created roundworm animal models carrying hyperactive ciliary kinases that disrupt cilia. Their genetic suppressor screens revealed that loss of an RNA adenosine deaminase that catalyzes adenosine-to-inosine (A-to-I) RNA editing rescued ciliary abnormalities. They found that kinase hyperactivation caused this RNA adenosine deaminase to edit kinase RNA and impair kinase RNA splicing and translation, thereby downregulating ciliary kinases from nuclei. These results suggest that ciliopathies may be treated by targeting the pathways outside of cilia.

Science, abd8971, this issue p. 984

Science: 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.

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