journal.pgen.1003279.PDF (8.08 MB)
Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis
journal contribution
posted on 2023-05-19, 04:30 authored by Boglev, Y, Badrock, AP, Andrew TrotterAndrew Trotter, Du, Q, Richardson, EJ, Parslow, AC, Markmiller, AJ, Hall, NE, de Jong-Curtain, TA, Ng, AY, Verkade, H, Ober, EA, Field, HA, Shin, D, Shin, CH, Hannan, KM, Pearson, RB, Kim, S-H, Ess, KC, Lieschke, GJ, Stainier, DYR, Heath, JKRibosome 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.
History
Publication title
PloS GeneticsVolume
9Article number
e1003279Number
e1003279Pagination
1-18ISSN
1553-7390Department/School
Institute for Marine and Antarctic StudiesPublisher
Public Library of SciencePlace of publication
United StatesRights statement
Copyright 2013 Boglev et al. Licensed under [unspecified] Creative Commons AttributionRepository Status
- Open