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<p><i>Cdk5 regulatory subunit-associated protein 1-like 1</i> (<i>Cdkal1</i>) encodes a tRNA-modifying enzyme responsible for thiomethylation generating 2-methylthio-<i>N</i><sup>6</sup>-threonylcarbamoyladenosine (ms<sup>2</sup>t<sup>6</sup>A) in the anticodon loop of tRNA<sup>Lys</sup><sub>UUU</sub>. Genome-wide association studies have identified <i>CDKAL1</i> variants as risk factors for type 2 diabetes mellitus (DM) and chronic kidney disease (CKD), but whether CKD arises independently of diabetes has remained elusive. Here, we demonstrate that CDKAL1 is required for kidney function and that its dysfunction directly promotes CKD progression independently of diabetes. Systemic and podocyte-specific <i>Cdkal1</i> knockout in mice leads to CKD phenotypes in later adulthood or after increasing the burden on&#xa0;kidney. <i>Cdkal1</i>-knockout podocytes show reduced lysine-codon translation and decreased levels of lysine-rich proteins, including such that are important for podocyte functions, accompanied by impaired cell migration. These adverse effects on podocytes could be partially reversed by overexpressing CD2AP, a lysine-rich protein. These findings extend the concept of ‘tRNA modopathy’ to kidney disease and provide mechanistic insights into how defective tRNA modification contributes to kidney disease progression.</p>

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CDKAL1 dysfunction impairs lysine codon translation in podocytes and accelerates chronic kidney disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • Hiroko Nagata,
  • Yu Nagayoshi,
  • Takeshi Chujo,
  • Hitomi Kaneko,
  • Kayo Nishiguchi,
  • Yutaka Kakizoe,
  • Hiroko Ijima,
  • Korin Sakakida,
  • Takeshi Masuda,
  • Sumio Ohtsuki,
  • Fan-Yan Wei,
  • Yukie Takahashi,
  • Takaichi Fukuda,
  • Hideaki Jinnouchi,
  • Yuki Adachi,
  • Ryosuke Yamamura,
  • Koki Matsushita,
  • Masataka Adachi,
  • Hideki Yokoi,
  • Kimitoshi Nakamura,
  • Hitoshi Nakazato,
  • Kazuhito Tomizawa

摘要

Cdk5 regulatory subunit-associated protein 1-like 1 (Cdkal1) encodes a tRNA-modifying enzyme responsible for thiomethylation generating 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in the anticodon loop of tRNALysUUU. Genome-wide association studies have identified CDKAL1 variants as risk factors for type 2 diabetes mellitus (DM) and chronic kidney disease (CKD), but whether CKD arises independently of diabetes has remained elusive. Here, we demonstrate that CDKAL1 is required for kidney function and that its dysfunction directly promotes CKD progression independently of diabetes. Systemic and podocyte-specific Cdkal1 knockout in mice leads to CKD phenotypes in later adulthood or after increasing the burden on kidney. Cdkal1-knockout podocytes show reduced lysine-codon translation and decreased levels of lysine-rich proteins, including such that are important for podocyte functions, accompanied by impaired cell migration. These adverse effects on podocytes could be partially reversed by overexpressing CD2AP, a lysine-rich protein. These findings extend the concept of ‘tRNA modopathy’ to kidney disease and provide mechanistic insights into how defective tRNA modification contributes to kidney disease progression.