Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis

Yeliz Boglev, Andrew P. Badrock, Andrew J. Trotter, Qian Du, Elsbeth J. Richardson, Adam C. Parslow, Sebastian J. Markmiller, Nathan E. Hall, Tanya A. de Jong-Curtain, Annie Y. Ng, Heather Verkade, Elke A. Ober, Holly A. Field, Donghun Shin, Chong H. Shin, Katherine M. Hannan, Ross D. Hannan, Richard B. Pearson, Seok Hyung Kim, Kevin C. EssGraham J. Lieschke, Didier Y.R. Stainier, Joan K. Heath

    Research output: Contribution to journalArticlepeer-review

    47 Citations (Scopus)
    5 Downloads (Pure)

    Abstract

    Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (ttis450), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In ttis450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in ttis450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in ttis450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.

    Original languageEnglish
    Article numbere1003279
    Pages (from-to)1-18
    Number of pages18
    JournalPLoS Genetics
    Volume9
    Issue number2
    DOIs
    Publication statusPublished - Feb 2013

    Bibliographical note

    Copyright the Author(s). Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

    Fingerprint

    Dive into the research topics of 'Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis'. Together they form a unique fingerprint.

    Cite this