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

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

51 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)e1004371
TijdschriftPLoS Genetics
Volume10
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 2014

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