Molecular Mechanisms of Autophagosome-Vacuole Fusion andDegradation of Peroxisomes by Autophagy

[摘要] Macroautophagy, hereafter referred to as autophagy, is a well-conserved cellular process among eukaryotes, through which portions of cytoplasm are degraded and recycled. Malfunction of autophagy has been related to many human diseases, including cancer, liver, heart and lung diseases and neurodegeneration. Therefore, it is important to study the molecular mechanisms of autophagy and how autophagy activity is regulated. Autophagy can be non selective or selective. Selective engulfment of peroxisomes by autophagy is termed pexophagy. Collaborating with Kai Mao, a previous Ph.D student in the lab, we determined that in mutants where peroxisome fission is compromised, pexophay is defective. The selective autophagy scaffold Atg11 and the pexophagy specific receptor Atg36 are able to interact with the fission machinery components including Dnm1 and Vps1 on peroxisomes being degraded. These findings imply that the autophagy machinery recruits peroxisome fission machinery to drive pexophay specific fission, facilitating efficient engulfment of the organelle.The later steps of the autophagy process involve fusion of the outer membrane of autophagosomes with the vacuole membrane. Working with Kai Mao, we confirmed an interaction between Atg17, a scaffold protein required for autophagy induction, and a vacuolar SNARE Vam7. The SNARE domain of Vam7 and several hydrophobic residues in helix1 and helix4 of Atg17 mediate the interaction. Specifically diminishing the interaction leads to defects in autophagosome-vacuole fusion and autophagic flux. This study provides new insights into the role of the Atg17-Atg31-Atg29 complex in the late stage of autophagy and how auophagosome-vacuole fusion is specifically regulated.

[发布机构] University of Michigan

[效力级别] Stress

[关键词] Autophagy;Stress;Pexophagy;Membrane fusion;Yeast;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular, and Developmental Biology