Molecular Mechanism and Regulation of Autophagy in Saccharomyces cerevisiae

[摘要] Macroautophagy (hereafter autophagy), literally defined as a type of self-eating, is a dynamic cellular process in which cytoplasm is sequestered within a unique compartment termed the phagophore. Upon completion, the phagophore matures into a double-membrane autophagosome that fuses with the lysosome or vacuole, allowing degradation of the cargo. Autophagy is involved in various aspects of cell physiology, and its dysregulation is associated with a range of diseases. Thus, Understanding of molecular mechanism and the regulation of autophagy is important for exploring potential therapy of diseases.The most prominent feature of autophagy is the formation of a double-membrane sequestering compartment, the phagophore; this transient organelle surrounds part of the cytoplasm and matures into an autophagosome, which subsequently fuses with the vacuole or lysosome to allow degradation of the cargo. Much attention has focused on the process involved in phagophore nucleation and expansion, but many questions remain. Here, we identified the yeast protein Icy2, which we now name Atg41, as playing a role in autophagosome formation. Atg41 interacts with the transmembrane protein Atg9, a key component involved in autophagosome biogenesis, and both proteins display a similar localization profile. Under autophagy-inducing conditions the expression level of Atg41 increases dramatically and is regulated by the transcription factor Gcn4. This work provides further insight into the mechanism of Atg9 function and the dynamics of sequestering membrane formation during autophagy.Autophagy is a tightly controlled cellular process by which cytosolic proteins, Studies have revealed the molecular mechanism of transcriptional regulation of autophagy-related (ATG) genes upon nutrient deprivation. However, little is known about their translational regulation. Here we found that Dhh1, a DExD/H-box RNA helicase, is required for efficient translation of Atg1 and Atg13, two proteins essential for autophagy induction. Dhh1 directly associates with ATG1 and ATG13 mRNAs under nitrogen starvation conditions. The structured regions shortly after the start codons of the two mRNAs are necessary for their regulation by Dhh1. Moreover, Eap1, an EIF4E binding protein, physically interacts with Dhh1 to facilitate the delivery of the Dhh1-ATG mRNA complex to the translation initiation machinery. These results suggest a model for how some ATG genes bypass the general translational suppression that occurs during nitrogen starvation to maintain a proper level of autophagy.The molecular mechansim of autophagosome formation has been an interesting topic over years due to its importance to autophagy process. This thesis enlarges the knowledge of Atg9 cycling system in yeast, which provides insight for understanding membrane donation process in autophagy. Diffterent levels of autophagy control are essential for cellular homestasis. This thesis, by investigating both transcriptional and translational regulation of autophagy, provides insight in understanding autophagy control. This will help further investigation on diseases resulting from autophagy dysfunction and their connections to autophagy regulation.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Autophagy;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular, and Developmental Biology