Atg1在細胞自噬和細胞凋亡之探討

Abstract

Atg1是一種絲氨酸/酥胺酸激脢。研究發現在酵母菌中，Atg1的激脢活性是CVT 訊息傳遞路徑以及細胞自噬所必須。Atg1可以和一些執行細胞自噬的蛋白質互相作用，而且有很多調控細胞自噬的訊息傳遞路徑會匯集在Atg1。因此Atg1可能是一個可以調控細胞自噬眾多步驟的一個調節點。但是在較高等的真核生物，Atg1的角色仍然不是很清楚。 目前已經知道細胞自噬可以導致細胞死亡，但是如何導致死亡的分子機制還不清楚。因此我利用果蠅為實驗材料，研究Atg1在細胞死亡中所扮演的角色。結果顯示在果蠅中，Atg1自己就足以引起細胞自噬和細胞凋零而導致細胞死亡。這個發現提供了一個直接的證據證明細胞自噬和細胞凋零在導致細胞死亡的過程中可能是互相影響的。另外，我找到一個未知的蛋白質dDlk。實驗結果顯示dDlk有能力引發細胞死亡。經由生化和遺傳分析，顯示dDlk可以和Atg1互相作用，且dDlk是位於Atg1引發細胞死亡訊息傳遞路徑的下游。我們正在調查Atg1如何調控dDlk的機制，藉此去建立Atg1和細胞死亡之間的關聯。

Atg1 encodes a Serine/Threonine kinase. In yeast, studies have found the requirement for Atg1 kinase activity in both CVT and autophagy. Atg1 interacts with multiple components of the autophagic machinery, and multiple signaling pathways converge on Atg1 to regulate autophagy. Thus, Atg1 is likely to represent a nodal point for controlling multiple steps in the autophagic process in response to various stresses. However, in higher eukaryotes, the role of Atg1 is still unclear. It has been shown that autophagy can induce cells death. However, the molecular mechanism underlying the autophagic cell death program is unclear. I have examined a potential role for Atg1 in cell death using Drosophila melanogaster as a model system. My results demonstrate that dAtg1 is sufficient to cause cell death due to the induction of autophagy and apoptosis. These findings provide a direct evidence that autophagy and apoptosis are interconnected. I have also identified a novel protein, dDlk. My results demonstrated that dDlk can induce cell death. The biochemical and genetic data reveal that dDlk interacts with dAtg1 and functions downstream of dAtg1-mediated cell death. Thus, dDlk may be an important downstream player in mediating dAtg1’s biological effects on promoting cell death. I am currently investigating whether dDlk is mediated by Atg1 and what is the biological function of Atg1 in cell death.