Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway

Harry F Heijnen, Richard van Wijk, Tamara C Pereboom, Yvonne J Goos, Cor W Seinen, Brigitte A van Oirschot, Rowie van Dooren, Marc Gastou, Rachel H Giles, Wouter van Solinge, Taco W Kuijpers, Hanna T Gazda, Marc B Bierings, Lydie Da Costa, Alyson W MacInnes

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)e1004371
JournalPLoS Genetics
Volume10
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • Anemia, Diamond-Blackfan
  • Animals
  • Autophagy
  • Bone Marrow Diseases
  • Erythropoiesis
  • Exocrine Pancreatic Insufficiency
  • Gene Expression Regulation, Developmental
  • Humans
  • Insulin
  • Lipomatosis
  • Mutation
  • Ribosomal Protein S6 Kinases
  • Ribosomal Proteins
  • Signal Transduction
  • Tumor Suppressor Protein p53
  • Zebrafish

Fingerprint

Dive into the research topics of 'Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway'. Together they form a unique fingerprint.

Cite this