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PLoS Genet DOI:10.1371/journal.pgen.1004371

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

Publication TypeJournal Article
Year of Publication2014
AuthorsHeijnen, HF, van Wijk, R, Pereboom, TC, Goos, YJ, Seinen, CW, van Oirschot, BA, van Dooren, R, Gastou, M, Giles, RH, van Solinge, W, Kuijpers, TW, Gazda, HT, Bierings, MB, Da Costa, L, MacInnes, AW
JournalPLoS Genet
Date Published2014
KeywordsAnemia, 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

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.


Alternate JournalPLoS Genet.
PubMed ID24875531
PubMed Central IDPMC4038485
Grant ListK02 HL111156 / HL / NHLBI NIH HHS / United States
K02HL111156 / HL / NHLBI NIH HHS / United States
R01HL107558 / HL / NHLBI NIH HHS / United States