Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo (original) (raw)

• Begun, J. & Xavier, R. J. Autophagy at the crossroads of metabolism and cellular defense. Curr. Opin. Gastroenterol. 29, 588–596 (2013).
  Article CAS PubMed Google Scholar
• Huang, J. & Brumell, J. H. Bacteria–autophagy interplay: a battle for survival. Nat. Rev. Microbiol. 12, 101–114 (2014).
  CAS PubMed PubMed Central Google Scholar
• Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• The Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
  Article CAS PubMed Central Google Scholar
• Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).
  Article CAS PubMed Google Scholar
• Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Metzger, S. et al. Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum. Genet. 128, 453–459 (2010).
  Article CAS PubMed Google Scholar
• Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
  Article CAS PubMed Google Scholar
• Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Klionsky, D. J. & Schulman, B. A. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat. Struct. Mol. Biol. 21, 336–345 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Obara, K., Noda, T., Niimi, K. & Ohsumi, Y. Transport of phosphatidylinositol 3-phosphate into the vacuole via autophagic membranes in Saccharomyces cerevisiae. Genes Cells 13, 537–547 (2008).
  Article CAS PubMed Google Scholar
• Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Matsunaga, K. et al. Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J. Cell Biol. 190, 511–521 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Polson, H. E. et al. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6, 506–522 (2010).
  Article CAS PubMed Google Scholar
• Mizushima, N., Yoshimori, T. & Ohsumi, Y. Role of the Apg12 conjugation system in mammalian autophagy. Int. J. Biochem. Cell Biol. 35, 553–561 (2003).
  Article CAS PubMed Google Scholar
• Johansen, T. & Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rogov, V., Dotsch, V., Johansen, T. & Kirkin, V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 53, 167–178 (2014).
  Article CAS PubMed Google Scholar
• Shaid, S., Brandts, C. H., Serve, H. & Dikic, I. Ubiquitination and selective autophagy. Cell Death Differ. 20, 21–30 (2013).
  Article CAS PubMed Google Scholar
• Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
  Article CAS PubMed Google Scholar
• Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Gillooly, D. J. et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 19, 4577–4588 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Folkes, A. J. et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 51, 5522–5532 (2008).
  Article CAS PubMed Google Scholar
• Maira, S. M. et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 11, 317–328 (2012).
  Article CAS PubMed Google Scholar
• Miller, S. et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638–1642 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nyfeler, B., Bergman, P., Wilson, C. J. & Murphy, L. O. Quantitative visualization of autophagy induction by mTOR inhibitors. Methods Mol. Biol. 821, 239–250 (2012).
  Article CAS PubMed Google Scholar
• Fujita, N. et al. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol. Biol. Cell 19, 4651–4659 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kirkin, V., McEwan, D. G., Novak, I. & Dikic, I. A role for ubiquitin in selective autophagy. Mol. Cell 34, 259–269 (2009).
  Article CAS PubMed Google Scholar
• Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009).
  Article CAS PubMed Google Scholar
• Thurston, T. L., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immu. 10, 1215–1221 (2009).
  Article CAS Google Scholar
• Newman, A. C. et al. TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1/Ndp52 and non-canonical NF-κB signalling. PLoS ONE 7, e50672 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Boada-Romero, E. et al. TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J. 32, 566–582 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ohzono, C. et al. Nedd4-interacting protein 2, a short half-life membrane protein degraded in lysosomes, negatively controls down-regulation of connexin43. Biol. Pharm. Bull. 33, 951–957 (2010).
  Article CAS PubMed Google Scholar
• Yeh, S. & Chang, C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc. Natl Acad. Sci. USA 93, 5517–5521 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Asano, T. et al. Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol. Cell. Biol. 31, 2040–2052 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bridges, K. R. Ascorbic acid inhibits lysosomal autophagy of ferritin. J. Biol. Chem. 262, 14773–14778 (1987).
  CAS PubMed Google Scholar
• Ericsson, J. L. Studies on induced cellular autophagy. I. Electron microscopy of cells with in vivo labelled lysosomes. Exp. Cell Res. 55, 95–106 (1969).
  Article CAS PubMed Google Scholar
• Mortensen, M. et al. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc. Natl Acad. Sci. USA 107, 832–837 (2010).
  Article CAS PubMed Google Scholar
• Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Seglen, P. O. & Gordon, P. B. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl Acad. Sci. USA 79, 1889–1892 (1982).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, Y. T. et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J. Biol. Chem. 285, 10850–10861 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Simonsen, A. & Tooze, S. A. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J. Cell Biol. 186, 773–782 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jaber, N. et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. USA 109, 2003–2008 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Morishita, H. et al. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J. Biol. Chem. 288, 11436–11447 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Parekh, V. V. et al. Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34. J. Immu. 190, 5086–5101 (2013).
  Article CAS Google Scholar
• Willinger, T. & Flavell, R. A. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc. Natl Acad. Sci. USA 109, 8670–8675 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, X. et al. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc. Natl Acad. Sci. USA 107, 9424–9429 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Devereaux, K. et al. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS ONE 8, e76405 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Crichton, R. R. & Declercq, J. P. X-ray structures of ferritins and related proteins. Biochim. Biophys. Acta 1800, 706–718 (2010).
  Article CAS PubMed Google Scholar
• Coffey, J. W. & DeDuve, C. Digestive activity of lysosomes. I. The digestion of proteins by extracts of rat liver lysosomes. J. Biol. Chem. 243, 3255–3263 (1968).
  CAS PubMed Google Scholar
• Andrews, S. C., Treffry, A. & Harrison, P. M. Siderosomal ferritin. The missing link between ferritin and haemosiderin? Biochem. J. 245, 439–446 (1987).
  Article CAS PubMed PubMed Central Google Scholar
• Ganz, T. & Nemeth, E. Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 62, 347–360 (2011).
  Article CAS PubMed Google Scholar
• Donovan, A., Roy, C. N. & Andrews, N. C. The ins and outs of iron homeostasis. Physiology (Bethesda) 21, 115–123 (2006).
  CAS Google Scholar
• Kidane, T. Z., Sauble, E. & Linder, M. C. Release of iron from ferritin requires lysosomal activity. Am. J. Physiol. Cell Physiol. 291, C445-455 (2006).
  Article CAS Google Scholar
• Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Gregory, A., Polster, B. J. & Hayflick, S. J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J. Med. Genet. 46, 73–80 (2009).
  Article CAS PubMed Google Scholar
• Levi, S., Cozzi, A. & Arosio, P. Neuroferritinopathy: a neurodegenerative disorder associated with L-ferritin mutation. Best Pract. Res. Clin. Haematol. 18, 265–276 (2005).
  Article CAS PubMed Google Scholar
• McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).
  CAS PubMed PubMed Central Google Scholar
• Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. 66, 213–221 (2010).
  Article CAS Google Scholar
• Proenca, C. C. et al. Atg4b-dependent autophagic flux alleviates Huntington’s disease progression. PLoS ONE 8, e68357 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Wee, S. et al. PTEN-deficient cancers depend on PIK3CB. Proc. Natl Acad. Sci. USA 105, 13057–13062 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Maira, S. M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 1851–1863 (2008).
  Article CAS PubMed Google Scholar
• Nyfeler, B. et al. Relieving autophagy and 4EBP1 from rapamycin resistance. Mol. Cell. Biol. 31, 2867–2876 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rush, J. et al. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat. Biotechnol. 23, 94–101 (2005).
  Article CAS PubMed Google Scholar
• Udeshi, N. D., Mertins, P., Svinkina, T. & Carr, S. A. Large-scale identification of ubiquitination sites by mass spectrometry. Nat. Protoc. 8, 1950–1960 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
  Article CAS PubMed Google Scholar
• Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794–1805 (2011).
  Article CAS PubMed Google Scholar