ALKBH3-dependent m1A demethylation of Aurora A mRNA inhibits ciliogenesis

Wenjun Kuang; Hao Jin; Feng Yang; Xiying Chen; Jianzhao Liu; Ting Li; Yongxia Chang; Min Liu; Zhangqi Xu; Chunxiao Huo; Xiaoyi Yan; Yuehong Yang; Wei Liu; Qiang Shu; Shanshan Xie; Tianhua Zhou

doi:10.1038/s41421-022-00385-3

ALKBH3-dependent m¹A demethylation of Aurora A mRNA inhibits ciliogenesis

Cell Discov. 2022 Mar 11;8(1):25. doi: 10.1038/s41421-022-00385-3.

Authors

Wenjun Kuang^#^{1

2}, Hao Jin^#^{1

2}, Feng Yang^#^{1

2}, Xiying Chen², Jianzhao Liu³, Ting Li³, Yongxia Chang², Min Liu², Zhangqi Xu², Chunxiao Huo², Xiaoyi Yan², Yuehong Yang², Wei Liu², Qiang Shu¹, Shanshan Xie⁴, Tianhua Zhou^{5

6

7}

Affiliations

¹ The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
² Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China.
⁴ The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China. sxie@zju.edu.cn.
⁵ Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. tzhou@zju.edu.cn.
⁶ Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. tzhou@zju.edu.cn.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. tzhou@zju.edu.cn.

^# Contributed equally.

Abstract

Primary cilia are antenna-like subcellular structures to act as signaling platforms to regulate many cellular processes and embryonic development. m¹A RNA modification plays key roles in RNA metabolism and gene expression; however, the physiological function of m¹A modification remains largely unknown. Here we find that the m¹A demethylase ALKBH3 significantly inhibits ciliogenesis in mammalian cells by its demethylation activity. Mechanistically, ALKBH3 removes m¹A sites on mRNA of Aurora A, a master suppressor of ciliogenesis. Depletion of ALKBH3 enhances Aurora A mRNA decay and inhibits its translation. Moreover, alkbh3 morphants exhibit ciliary defects, including curved body, pericardial edema, abnormal otoliths, and dilation in pronephric ducts in zebrafish embryos, which are significantly rescued by wild-type alkbh3, but not by its catalytically inactive mutant. The ciliary defects caused by ALKBH3 depletion in both vertebrate cells and embryos are also significantly reversed by ectopic expression of Aurora A mRNA. Together, our data indicate that ALKBH3-dependent m¹A demethylation has a crucial role in the regulation of Aurora A mRNA, which is essential for ciliogenesis and cilia-associated developmental events in vertebrates.