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First published online 29 August 2006
doi: 10.1242/jcs.03172
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Research Article |
1 Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
2 Faculty of Life Sciences, University of Manchester, Smith Building, Oxford Road, Manchester, M13 9PT, UK
3 NIH / NICHD / CBMB, Bldg 18T Room 101, 9000 Rockville Pike, Bethesda, MD, 20892, USA
* Author for correspondence (e-mail: Sharon.tooze{at}cancer.org.uk)
Accepted 11 July 2006
Autophagy, fundamentally a lysosomal degradation pathway, functions in cells during normal growth and certain pathological conditions, including starvation, to maintain homeostasis. Autophagosomes are formed through a mechanism that is not well understood, despite the identification of many genes required for autophagy. We have studied the mammalian homologue of Atg9p, a multi-spanning transmembrane protein essential in yeast for autophagy, to gain a better understanding of the function of this ubiquitious protein. We show that both the N- and C-termini of mammalian Atg9 (mAtg9) are cytosolic, and predict that mAtg9 spans the membrane six times. We find that mAtg9 is located in the trans-Golgi network and late endosomes and colocalizes with TGN46, the cation-independent mannose-6-phosphate receptor, Rab7 and Rab9. Amino acid starvation or rapamycin treatment, which upregulates autophagy, causes a redistribution of mAtg9 from the TGN to peripheral, endosomal membranes, which are positive for the autophagosomal marker GFP-LC3. siRNA-mediated depletion of the putative mammalian homologue of Atg1p, ULK1, inhibits this starvation-induced redistribution. The redistribution of mAtg9 also requires PI 3-kinase activity, and is reversed after restoration of amino acids. We speculate that starvation-induced autophagy, which requires mAtg9, may rely on an alteration of the steady-state trafficking of mAtg9, in a Atg1-dependent manner.
Key words: Autophagy, Golgi, Rab proteins, Intracellular transport, Transmembrane protein
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