Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway
| Autor: | Lydie Da Costa, Tamara C. Pereboom, Wouter W. van Solinge, Marc Gastou, Taco W. Kuijpers, Rachel H. Giles, Brigitte A. van Oirschot, Hanna T. Gazda, Rowie van Dooren, Alyson W. MacInnes, Richard van Wijk, Harry F. G. Heijnen, Yvonne J. Goos, Cor W. Seinen, Marc Bierings |
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| Přispěvatelé: | Amsterdam institute for Infection and Immunity, Paediatric Infectious Diseases / Rheumatology / Immunology, Other departments, Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Cell signaling 0302 clinical medicine Diamond-Blackfan Molecular Cell Biology Insulin Lipomatosis Erythropoiesis Developmental Bone Marrow Diseases Genetics (clinical) Zebrafish Anemia Diamond-Blackfan 0303 health sciences biology Kinase Gene Expression Regulation Developmental Anemia Shwachman-Diamond Syndrome Cell biology 030220 oncology & carcinogenesis Phosphorylation Signal transduction Research Article Signal Transduction Ribosomal Proteins lcsh:QH426-470 03 medical and health sciences Genetics Autophagy Animals Humans Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology TOR signaling Biology and life sciences Ribosomal Protein S6 Kinases HEK 293 cells Molecular Development lcsh:Genetics Insulin receptor Gene Expression Regulation Genetics of Disease Mutation biology.protein Exocrine Pancreatic Insufficiency Gene Function Tumor Suppressor Protein p53 Insulin-Dependent Signal Transduction Developmental Biology |
| Zdroj: | PLoS Genetics PLoS genetics, 10(5). Public Library of Science PLoS Genetics, 10(5). Public Library of Science PLoS Genetics, Vol 10, Iss 5, p e1004371 (2014) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies. Author Summary Diseases linked to mutations affecting the ribosome, ribosomopathies, have an exceptionally wide range of phenotypes. However, many ribosomopathies have some features in common including cytopenia and growth defects. Our study aims to clarify the mechanisms behind these common phenotypes. We find that mutations in ribosomal protein genes result in a series of aberrant signaling events that cause cells to start recycling and consuming their own intracellular contents. This basic mechanism of catabolism is activated when cells are starving for nutrients, and also during the tightly regulated process of blood cell maturation. The deregulation of this mechanism provides an explanation as to why blood cells are so acutely affected by mutations in genes that impair the ribosome. Moreover, we find that the signals activating this catabolism are coupled to impairment of the highly conserved insulin-signaling pathway that is essential for growth. Taken together, our in-depth description of the pathways involved as the result of mutations affecting the ribosome increases our understanding about the etiology of these diseases and opens up previously unknown avenues of potential treatment. |
| Databáze: | OpenAIRE |
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