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.
Highlights
The generation of new ribosomes is the most energy-consuming process in the cell [1]
An understanding of the wide spectrum of physiological stimuli that can trigger this beneficial cellular mechanism is only just starting to emerge. This process has a negative side, since autophagy is exploited in certain pathological conditions, including cancer, to extend the lifespan of cells that would otherwise die
In, an inherited mutation in a gene required for ribosome production provides a powerful stimulus to autophagy in affected tissues, allowing them to evade cell death
Summary
The generation of new ribosomes is the most energy-consuming process in the cell [1]. It requires the coordinated transcription and maturation of 4 different ribosomal RNA (rRNA) molecules and 70 small nucleolar RNAs (snoRNAs) together with the synthesis of approximately 80 ribosomal proteins (RPs) and an additional 170 associated proteins [2]. The regulation of this complex, multi-step process is the major factor determining the potential of a cell to grow and divide [3]. Ribosome biogenesis is downregulated to conserve energy and restrict unwarranted cell growth
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