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Molecular cell v.65 no.4, 2017년, pp.751 - 760.e4   SCI SCIE
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ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation

Sundaramoorthy, Elayanambi (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Leonard, Marilyn (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Mak, Raymond (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Liao, Jeffrey (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Fulzele, Amitkumar (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Bennett, Eric J. (Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ;
  • 초록  

    Summary 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. Highlights Poly(A) sequences stall ribosomes and repress downstream translation in mammals Ribosome stall resolution requires regulatory ubiquitylation of RPS10 and RPS20 ZNF598 and RACK1 are needed for initiation of ribosome stall resolution in mammals ZNF598 catalyzes regulatory ribosomal ubiquitylation of RPS20, RPS10, and RPS3 Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    ubiquitin .   ribosome-associated quality control .   protein homeostasis .   translation control .   protein modification.  

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