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Peer-reviewedCC BY-NCScience Advances

NAT10 governs development through the Xrp1-mediated stress response rather than its RNA acetylation activity

  • Lin Wang1
  • Zhao Xue1
  • Shuyang Gao1
  • Yanhua Wang1
  • Houguang Lu1
  • Bo Peng2
  • Tianyi Fan1
  • Ying Cao1
  • Jian-Quan Ni2
  • Guoliang Lu1
  • Jinzhong Lin1
  • Dong Yan1
  1. 1State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai 200438, China.
  2. 2Gene Regulatory Lab, School of Medicine, Tsinghua University, Beijing 100084, China.
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Abstract

N 4 -acetylcytidine (ac 4 C) is installed by N -acetyltransferase 10 (NAT10) and represents the only known acetylation mark on messenger RNA. Since NAT10 also acetylates transfer RNA, ribosomal RNA (rRNA), and proteins, its in vivo molecular mechanisms remain elusive. Here, we demonstrate that knockdown of Drosophila NAT10 induces an eye-to-antenna transformation, c-Jun amino-terminal kinase activation, and cell apoptosis. NAT10 facilitates ac 4 C modification in rRNA, and its loss impairs rRNA processing and ribosomal assembly. Depletion of NAT10 activates the integrated stress response, ultimately leading to reduced global protein synthesis. Crucially, Xrp1 plays a key role in the stress response and its ablation rescues most NAT10 loss-of-function defects and transcriptomic alterations. We also performed acetylated RNA immunoprecipitation and sequencing (acRIP-seq) on control and NAT10 knockdown flies. Furthermore, a catalytically deficient form of NAT10, which is unable to mediate ac 4 C acetylation, completely rescues the lethality of NAT10 mutants. Collectively, these findings establish that NAT10’s primary developmental function stems from its roles in ribosome biogenesis and Xrp1 activation, which are independent of its RNA acetylation activity.

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Cite

BibTeXRIS
BibTeX
@article{wang2026nat10,
  title = {{NAT10 governs development through the Xrp1-mediated stress response rather than its RNA acetylation activity}},
  author = {Lin Wang and Zhao Xue and Shuyang Gao and Yanhua Wang and Houguang Lu and Bo Peng and Tianyi Fan and Ying Cao and Jian-Quan Ni and Guoliang Lu and Jinzhong Lin and Dong Yan},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeg0399},
  url = {https://www.science.org/doi/10.1126/sciadv.aeg0399},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - NAT10 governs development through the Xrp1-mediated stress response rather than its RNA acetylation activity
AU  - Lin Wang
AU  - Zhao Xue
AU  - Shuyang Gao
AU  - Yanhua Wang
AU  - Houguang Lu
AU  - Bo Peng
AU  - Tianyi Fan
AU  - Ying Cao
AU  - Jian-Quan Ni
AU  - Guoliang Lu
AU  - Jinzhong Lin
AU  - Dong Yan
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aeg0399
UR  - https://www.science.org/doi/10.1126/sciadv.aeg0399
AB  - N 4 -acetylcytidine (ac 4 C) is installed by N -acetyltransferase 10 (NAT10) and represents the only known acetylation mark on messenger RNA. Since NAT10 also acetylates transfer RNA, ribosomal RNA (rRNA), and proteins, its in vivo molecular mechanisms remain elusive. Here, we demonstrate that knockdown of Drosophila NAT10 induces an eye-to-antenna transformation, c-Jun amino-terminal kinase activation, and cell apoptosis. NAT10 facilitates ac 4 C modification in rRNA, and its loss impairs rRNA processing and ribosomal assembly. Depletion of NAT10 activates the integrated stress response, ultimately leading to reduced global protein synthesis. Crucially, Xrp1 plays a key role in the stress response and its ablation rescues most NAT10 loss-of-function defects and transcriptomic alterations. We also performed acetylated RNA immunoprecipitation and sequencing (acRIP-seq) on control and NAT10 knockdown flies. Furthermore, a catalytically deficient form of NAT10, which is unable to mediate ac 4 C acetylation, completely rescues the lethality of NAT10 mutants. Collectively, these findings establish that NAT10’s primary developmental function stems from its roles in ribosome biogenesis and Xrp1 activation, which are independent of its RNA acetylation activity.
SN  - 2375-2548
ER  -