Macro-autophagy is the intracellular stress-response pathway by which the cell packages portions of the cytosol for delivery into the lysosome. This """"""""packaging"""""""" is carried out by the de novo formation of a new organelle called the autophagosome that grows and encapsulates cytosolic material for eventual lysosomal degradation. How autophagosomes form, including especially how the membrane expands and eventually closes upon itself is an area of intense study. One factor implicated in these activitie is the ubiquitin-like protein, Atg8. During autophagy, Atg8 becomes covalently bound to phosphatidylethanolamine (PE) on the preautophagosomal membrane and remains bound through the maturation process of the autophagosome. Our preliminary results suggest that Atg8-PE is a central figure in deforming the membrane perhaps as a prelude to determining sites of membrane tethering or membrane fusion. Here we will build on these results to determine how Atg8 might control each of the membrane dynamics that underlie the late steps of autophagosome maturation.

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The regulation of membrane dynamics underlies the growth, bending, budding, and fusion of intracellular organelles. However, how these events occur on the maturing autophagosome, including the ultimate fusion-dependent closure of the autophagosome is not yet known. To this end, we have several recent results implicating the Atg8 family of autophagy proteins in the control of membrane dynamics. Here we propose to develop novel biochemical reconstitutions and biophysical approaches to establish what protein and membrane compositions support Atg8-mediated dynamics including the roles of membrane architecture and the potential for competitive interactions with Atg8-binding proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Chin, Jean
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Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
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