Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects

Yu Shi (), Daochao Huang, Cui Song, Ruixue Cao, Zhao Wang, Dan Wang, Li Zhao, Xiaolu Xu, Congyu Lu, Feng Xiong, Haowen Zhao, Shuxiang Li, Quansheng Zhou, Shuyue Luo, Dongjie Hu, Yun Zhang, Cui Wang, Yiping Shen, Weiting Su, Yili Wu, Karl Schmitz, Shuo Wei () and Weihong Song ()
Additional contact information
Yu Shi: Children’s Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders
Daochao Huang: Children’s Hospital of Chongqing Medical University
Cui Song: Children’s Hospital of Chongqing Medical University
Ruixue Cao: Wenzhou Medical University
Zhao Wang: Wenzhou Medical University
Dan Wang: Children’s Hospital of Chongqing Medical University
Li Zhao: Children’s Hospital of Chongqing Medical University
Xiaolu Xu: University of Delaware
Congyu Lu: University of Delaware
Feng Xiong: Children’s Hospital of Chongqing Medical University
Haowen Zhao: Children’s Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders
Shuxiang Li: Children’s Hospital of Chongqing Medical University
Quansheng Zhou: Children’s Hospital of Chongqing Medical University
Shuyue Luo: Children’s Hospital of Chongqing Medical University
Dongjie Hu: Children’s Hospital of Chongqing Medical University
Yun Zhang: Children’s Hospital of Chongqing Medical University
Cui Wang: Children’s Hospital of Chongqing Medical University
Yiping Shen: Boston Children’s Hospital and Harvard Medical School
Weiting Su: Chinese Academy of Science
Yili Wu: Wenzhou Medical University
Karl Schmitz: University of Delaware
Shuo Wei: University of Delaware
Weihong Song: Wenzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient’s mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient’s mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Date: 2024
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DOI: 10.1038/s41467-024-47670-1

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