2. Academic Validation
  3. ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains

ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains

  • Mol Cell. 2020 May 21;78(4):700-713.e7. doi: 10.1016/j.molcel.2020.03.021.
Anna Constance Vind 1,  Goda Snieckute 1,  Melanie Blasius 1,  Christopher Tiedje 1,  Nicolai Krogh 2,  Dorte Breinholdt Bekker-Jensen 3,  Kasper Langebjerg Andersen 4,  Cathrine Nordgaard 1,  Maxim Alexander Xavier Tollenaere 1,  Anders Henrik Lund 4,  Jesper Velgaard Olsen 3,  Henrik Nielsen 2,  Simon Bekker-Jensen 5
Affiliations

Affiliations

  • 1 Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 2 Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 3 Mass Spectrometry for Quantitative Proteomics, Proteomics Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
  • 4 Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
  • 5 Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address: [email protected].
PMID: 32289254 DOI: 10.1016/j.molcel.2020.03.021
Abstract

Impairment of ribosome function activates the MAPKKK ZAK, leading to activation of mitogen-activated protein (MAP) kinases p38 and JNK and inflammatory signaling. The mechanistic basis for activation of this ribotoxic stress response (RSR) remains completely obscure. We show that the long isoform of ZAK (ZAKα) directly associates with ribosomes by inserting its flexible C terminus into the ribosomal intersubunit space. Here, ZAKα binds helix 14 of 18S ribosomal RNA (rRNA). An adjacent domain in ZAKα also probes the ribosome, and together, these sensor domains are critically required for RSR activation after inhibition of both the E-site, the peptidyl transferase center (PTC), and ribotoxin action. Finally, we show that ablation of the RSR response leads to organismal phenotypes and decreased lifespan in the nematode Caenorhabditis elegans (C. elegans). Our findings yield mechanistic insight into how cells detect ribotoxic stress and provide experimental in vivo evidence for its physiological importance.

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