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

PLoS Genet. 2014 May 29;10(5):e1004371. doi: 10.1371/journal.pgen.1004371. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*
  • Shwachman-Diamond Syndrome
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Zebrafish / genetics
  • Zebrafish / growth & development

Substances

  • Insulin
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • ribosomal protein S19
  • Ribosomal Protein S6 Kinases

Supplementary concepts

  • Shwachman syndrome