Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis

Ji Geng (), Shuangxi Li, Yu Li, Zhihao Wu, Sunil Bhurtel, Suman Rimal, Danish Khan, Rani Ohja, Onn Brandman and Bingwei Lu ()
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Ji Geng: Stanford University School of Medicine
Shuangxi Li: Stanford University School of Medicine
Yu Li: Stanford University School of Medicine
Zhihao Wu: Stanford University School of Medicine
Sunil Bhurtel: Stanford University School of Medicine
Suman Rimal: Stanford University School of Medicine
Danish Khan: Stanford University School of Medicine
Rani Ohja: Stanford University School of Medicine
Onn Brandman: Stanford University School of Medicine
Bingwei Lu: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45525-3

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