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Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
Geng, Ji; Li, Shuangxi; Li, Yu; Wu, Zhihao; Bhurtel, Sunil; Rimal, Suman; Khan, Danish; Ohja, Rani; Brandman, Onn; Lu, Bingwei.
Afiliação
  • Geng J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA. jigeng@stanford.edu.
  • Li S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Li Y; Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, 266237, China.
  • Wu Z; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Bhurtel S; Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, 266237, China.
  • Rimal S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Khan D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Ohja R; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Brandman O; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Lu B; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun ; 15(1): 1637, 2024 Feb 22.
Article em En | MEDLINE | ID: mdl-38388640
ABSTRACT
Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biossíntese de Proteínas / Proteínas de Saccharomyces cerevisiae Limite: Animals / Humans Idioma: En Revista: Nat Commun Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biossíntese de Proteínas / Proteínas de Saccharomyces cerevisiae Limite: Animals / Humans Idioma: En Revista: Nat Commun Ano de publicação: 2024 Tipo de documento: Article