ZNF598 responds to mitochondrial stress to abort stalled translation on mitochondrial outer membrane and maintain tissue homeostasis

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 and its level is upregulated upon mitochondrial stress in mammalian cells and Drosophila. Overexpression of ZNF598 protects against mitochondrial stress. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborted stalled translation of mitochondrial outer membrane-associated mRNAs and removed faulty translation products causal of disease. These results shed lights on the regulation of ZNF598 and its important role in mitochondrial homeostasis.