2. Academic Validation
  3. m6Am methyltransferase PCIF1 negatively regulates ciliation by inhibiting BICD2 expression

m6Am methyltransferase PCIF1 negatively regulates ciliation by inhibiting BICD2 expression

  • J Cell Biol. 2024 Jun 3;223(6):e202307002. doi: 10.1083/jcb.202307002.
Shanshan Xie # 1,  Wenjun Kuang # 2,  Mengzhe Guo # 3,  Feng Yang # 1,  Hao Jin 4,  Xiying Chen 4,  Li Yi 4,  Chunxiao Huo 4,  Zhangqi Xu 1,  Aifu Lin 5,  Wei Liu 6,  Jianhua Mao 1,  Qiang Shu 1,  Tianhua Zhou 4
Affiliations

Affiliations

  • 1 Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
  • 3 School of Pharmacy, Xuzhou Medical University, Xuzhou, China.
  • 4 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 6 Metabolic Medicine Center, International Institutes of Medicine and the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
  • # Contributed equally.
PMID: 38526325 DOI: 10.1083/jcb.202307002
Abstract

N6, 2'-O-dimethyladenosine (m6Am) is a widespread RNA modification catalyzed by the methyltransferase PCIF1 (phosphorylated CTD interacting factor 1). Despite its prevalence, the biological functions of m6Am in RNA remain largely elusive. Here, we report a critical role of PCIF1-dependent m6Am RNA modification in ciliogenesis in RPE-1 cells. Our findings demonstrate that PCIF1 acts as a negative regulator of ciliation through its m6Am methyltransferase activity. A quantitative proteomic analysis identifies BICD2 as a downstream target of PCIF1, with PCIF1 depletion resulting in a significant increase in BICD2 levels. BICD2 depletion leads to a significant reduction in ciliation. Crucially, the ciliary phenotype in PCIF1-depleted cells is reversed upon BICD2 knockdown. Further investigations reveal that PCIF1 regulates BICD2 protein levels through its m6Am catalytic activity, which reduces the stability and translation efficiency of BICD2 mRNA. Single-base resolution LC-MS analysis identifies the m6Am site on BICD2 mRNA modified by PCIF1. These findings establish the essential involvement of PCIF1-dependent m6Am modification in ciliogenesis.

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