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Regulation of mammalian autophagy via mAtg9 and p38IP

Webber, J.L.; (2010) Regulation of mammalian autophagy via mAtg9 and p38IP. Doctoral thesis, UCL (University College London).

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Abstract

Autophagy is a lysosomal degradation pathway that is essential for homeostasis, development and disease. It is characterised by an elongating membrane that enwraps a portion of the cytoplasm to form a double membrane vesicle termed an autophagosome. Autophagosomes are then delivered to the endocytic pathway and/or lysosome for degradation and recycling of the sequestered cargo. Identification of 31 autophagy-related proteins (Atg), including the transmembrane protein Atg9, has led to the recent advancement in understanding the molecular mechanisms that govern autophagy. However, a number of questions remain unanswered, including the origin of the donor membrane and the specificity of the cargo selected. Atg9 is required for autophagy in both yeast and mammalian cells and has been speculated to be involved in delivery of membrane lipids to forming autophagosomes. In mammalian cells, mAtg9 traffics between the trans-Golgi network, endosomes and newly formed autophagosomes. To better understand the mechanisms involved in regulation of mAtg9 trafficking I performed a yeast two-hybrid screen and identified p38IP as an interacting partner of the C-terminal domain of mAtg9. p38IP was originally identified as a p38alpha interacting protein and was shown to be required for p38alpha activation in mouse development. Here, I show that p38IP is required for mAtg9 trafficking and autophagosome formation. Furthermore, I find that the interaction between mAtg9 and p38IP is regulated by p38alpha, a negative regulator of autophagy in HEK293 cells. Following activation of p38alpha with anisomycin, binding of p38IP to mAtg9 is disrupted and autophagy inhibited. I propose a model by which p38alpha regulates interaction of p38IP with mAtg9, and as a result regulates mAtg9 trafficking and autophagosome formation.

Type:Thesis (Doctoral)
Title:Regulation of mammalian autophagy via mAtg9 and p38IP
Language:English
Additional information:Authorisation for digitisation not received

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