PUBLICATION

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Authors
Heijnen, H.F., van Wijk, R., Pereboom, T.C., Goos, Y.J., Seinen, C.W., van Oirschot, B.A., van Dooren, R., Gastou, M., Giles, R.H., van Solinge, W., Kuijpers, T.W., Gazda, H.T., Bierings, M.B., Da Costa, L., MacInnes, A.W.
ID
ZDB-PUB-140531-7
Date
2014
Source
PLoS Genetics   10: e1004371 (Journal)
Registered Authors
Pereboom, Tamara
Keywords
Embryos, Autophagic cell death, Insulin, HEK 293 cells, Zebrafish, Insulin signaling, Mitochondria, Small interfering RNAs
MeSH Terms
  • Anemia, Diamond-Blackfan/genetics*
  • Anemia, Diamond-Blackfan/pathology
  • Animals
  • Autophagy/genetics
  • Bone Marrow Diseases/genetics*
  • Bone Marrow Diseases/pathology
  • Erythropoiesis/genetics
  • Exocrine Pancreatic Insufficiency/genetics*
  • Exocrine Pancreatic Insufficiency/pathology
  • Gene Expression Regulation, Developmental
  • Humans
  • Insulin/genetics
  • Insulin/metabolism*
  • Lipomatosis/genetics*
  • Lipomatosis/pathology
  • Mutation
  • Ribosomal Protein S6 Kinases/antagonists & inhibitors
  • Ribosomal Protein S6 Kinases/genetics*
  • Ribosomal Proteins/genetics
  • Ribosomal Proteins/metabolism*
  • Signal Transduction/drug effects
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/genetics
  • Zebrafish/growth & development
(all 25)
PubMed
24875531 Full text @ PLoS Genet.
Abstract
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.
Genes / Markers
Marker Marker Type Name
rpl11GENEribosomal protein L11
rps3aGENEribosomal protein S3A
rps7GENEribosomal protein S7
tp53GENEtumor protein p53
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Figures
Figure Gallery (10 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi1034bTgTransgenic Insertion
hi1290TgTransgenic Insertion
hi3820bTgTransgenic Insertion
zdf1
    Point Mutation
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    Diamond-Blackfan anemiaTAS
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    Sequence Targeting Reagents
    No data available
    Fish
    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-rps7monoclonalIgG1Mouse
    Ab1-rps19monoclonal
      IgG2bMouse
      Ab5-sqstm1polyclonal
        Guinea pig
        Ab6-rps6kmonoclonal
          IgGRabbit
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          Orthology
          No data available
          Engineered Foreign Genes
          No data available
          Mapping
          No data available