ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation

Mol Cell. 2017 Feb 16;65(4):751-760.e4. doi: 10.1016/j.molcel.2016.12.026. Epub 2017 Jan 26.


Ribosomes that experience terminal stalls during translation are resolved by ribosome-associated quality control (QC) pathways that oversee mRNA and nascent chain destruction and recycle ribosomal subunits. The proximal factors that sense stalled ribosomes and initiate mammalian ribosome-associated QC events remain undefined. We demonstrate that the ZNF598 ubiquitin ligase and the 40S ribosomal protein RACK1 help to resolve poly(A)-induced stalled ribosomes. They accomplish this by regulating distinct and overlapping regulatory 40S ribosomal ubiquitylation events. ZNF598 primarily mediates regulatory ubiquitylation of RPS10 and RPS20, whereas RACK1 regulates RPS2, RPS3, and RPS20 ubiquitylation. Gain or loss of ZNF598 function or mutations that block RPS10 or RPS20 ubiquitylation result in defective resolution of stalled ribosomes and subsequent readthrough of poly(A)-containing stall sequences. Together, our results indicate that ZNF598, RACK1, and 40S regulatory ubiquitylation plays a pivotal role in mammalian ribosome-associated QC pathways.

Keywords: protein homeostasis; protein modification; ribosome-associated quality control; translation control; ubiquitin.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein Biosynthesis*
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Ribosomes / enzymology*
  • Ribosomes / genetics
  • Transfection
  • Ubiquitin / metabolism*
  • Ubiquitination*


  • Carrier Proteins
  • Neoplasm Proteins
  • RACK1 protein, human
  • RNA, Messenger
  • RPS3 protein, human
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Ribosomal Proteins
  • Ubiquitin
  • ZNF598 protein, human
  • ribosomal protein S10
  • ribosomal protein S20
  • GTP-Binding Proteins