Boglev, YelizBadrock, Andrew P.Trotter, Andrew J.Du, QianRichardson, Elsbeth J.Parslow, Adam C.Markmiller, Sebastian J.Hall, Nathan E.de Jong-Curtain, Tanya A.Ng, Annie Y.Verkade, HeatherOber, Elke A.Field, Holly A.Shin, DonghunShin, Chong H.Hannan, KatherineHannan, Ross D.Pearson, Richard B.Kim, Seok-HyungEss, Kevin C.Lieschke, Graham J.Stainier, Didier Y. R.Heath, Joan K.2016-01-252016-01-251553-7404http://hdl.handle.net/1885/95654Ribosome 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 (tti(s450)), 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 tti(s450), 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 tti(s450) larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in tti(s450) 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.This research was funded by the National Health and Medical Research Council of Australia through Project grant 433614 (JKH), Program grant 487922 (JKH), a Senior Research Fellowship (JKH), and a Howard Florey Centenary Fellowship (HV). Operational Infrastructure Support was provided by the Victorian Government, Australia. Additional support was from Australian Research Council grant DP0346823 (GJL); NIH grant DK060322 (DYRS); and CDMRP, Department of Defense, USA W81XWH-10-1-0854 (KCE).© 2013 Boglev et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.animalsautophagycell survivalgenes, lethalmutationprotein biosynthesisrna, ribosomal, 18szebrafishcell cycle proteinsribosomestor serine-threonine kinasestumor suppressor protein p53zebrafish proteins2013-02-0710.1371/journal.pgen.10032792018-11-29