title: Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.
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 (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.
authors: Colon Molecular and Cellular Biology Laboratory, Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Melbourne, Victoria, Australia.
authors: Yeliz
authors: Y
authors: Boglev
authors: Andrew P
authors: AP
authors: Badrock
authors: Andrew J
authors: AJ
authors: Trotter
authors: Qian
authors: Q
authors: Du
authors: Elsbeth J
authors: EJ
authors: Richardson
authors: Adam C
authors: AC
authors: Parslow
authors: Sebastian J
authors: SJ
authors: Markmiller
authors: Nathan E
authors: NE
authors: Hall
authors: Tanya A
authors: TA
authors: de Jong-Curtain
authors: Annie Y
authors: AY
authors: Ng
authors: Heather
authors: H
authors: Verkade
authors: Elke A
authors: EA
authors: Ober
authors: Holly A
authors: HA
authors: Field
authors: Donghun
authors: D
authors: Shin
authors: Chong H
authors: CH
authors: Shin
authors: Katherine M
authors: KM
authors: Hannan
authors: Ross D
authors: RD
authors: Hannan
authors: Richard B
authors: RB
authors: Pearson
authors: Seok-Hyung
authors: SH
authors: Kim
authors: Kevin C
authors: KC
authors: Ess
authors: Graham J
authors: GJ
authors: Lieschke
authors: Didier Y R
authors: DY
authors: Stainier
authors: Joan K
authors: JK
authors: Heath
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D005804:Genes, Lethal / Q000235:genetics; D009154:Mutation; D014176:Protein Biosynthesis / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D012337:RNA, Ribosomal, 18S; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C570686:periodic tryptophan protein 2 gene homologue, zebrafish; D058570:TOR Serine-Threonine Kinases