| Summary: | 碩士 === 國立臺灣大學 === 分子醫學研究所 === 102 === Autophagy, a cellular self-eating mechanism, is important for maintaining homeostasis and recycling cytosolic materials in response to various stresses such as starvation. ULK1 is the most critical protein kinase whose function in autophagy spans throughout early to late stage. However, the regulatory mechanism of ULK1 remains largely elusive. In this thesis, we discovered a novel ubiquitin-proteasomal regulation of ULK1 mediated by Cul3-KLHL20 complex, an E3 ubiquitin ligase. At nutrient rich conditions, we demonstrated that Cul3-KLHL20 promotes ULK1 ubiquitination and degradation, and thus controls the activity of basal autophagy. More importantly, we showed that KLHL20-mediated ULK1 degradation is stimulated by the activation of autophagy. During starvation, KLHL20 and ULK1 interaction is gradually increased while the amount of ULK1 is gradually decreased. The similar mode of ULK1 regulation occurs during autophagy induced by ER stress, mitochondria damage and other stress conditions. We further showed that this KLHL20-dependent ULK1 regulation controls the amplitude and duration of autophagy to prevent prolonged or overly activated autophagy. This study identifies a novel regulatory mechanism for ULK1 and suggests a key role of this regulation in maintaining cell homeostasis.
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