TY - JOUR

T1 - Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis

AU - Boglev, Yeliz

AU - Badrock, Andrew P

AU - Trotter, Andrew J

AU - Du, Qian

AU - Richardson, Elsbeth J

AU - Parslow, Adam C

AU - Markmiller, Sebastian J

AU - Hall, Nathan E

AU - de Jong-Curtain, Tanya A

AU - Ng, Annie Y

AU - Verkade, Heather

AU - Ober, Elke A

AU - Field, Holly A

AU - Shin, Donghun

AU - Shin, Chong H

AU - Hannan, Katherine M

AU - Hannan, Ross D

AU - Pearson, Richard B

AU - Kim, Seok-Hyung

AU - Ess, Kevin C

AU - Lieschke, Graham J

AU - Stainier, Didier Y R

AU - Heath, Joan K

PY - 2013

Y1 - 2013

N2 - 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 (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.

AB - 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 (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.

KW - Animals

KW - Autophagy

KW - Cell Cycle Proteins

KW - Cell Survival

KW - Genes, Lethal

KW - Mutation

KW - Protein Biosynthesis

KW - RNA, Ribosomal, 18S

KW - Ribosomes

KW - TOR Serine-Threonine Kinases

KW - Tumor Suppressor Protein p53

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1371/journal.pgen.1003279

DO - 10.1371/journal.pgen.1003279

M3 - Journal article

C2 - 23408911

VL - 9

SP - e1003279

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 2

ER -