细胞自噬中的新蛋白质机器的鉴定和研究

Identification and Functional Studies of New Autophagy Protein Machinary

细胞自噬是进化保守的,基于溶酶体的胞内降解途径,对维持细胞的稳态平衡有重要作用。自噬参与生物体发育、免疫反应、代谢调节、细胞凋亡和衰老等多种过程。自噬异常与神经退行性疾病、肿瘤等的发生密切相关。自噬是当今生命科学领域的研究热点之一。1992年大隅良典实验室利用酵母遗传筛选鉴定了15个自噬核心基因,也因此获得2016年度诺贝尔生理学或医学奖。当前自噬领域研究的重点集中在酵母以及通过酵母遗传筛选获得的核心蛋白质机器。然而单细胞酵母、单一诱导条件为出发点的筛选和研究具有明显的局限性。本文将从自噬过程的细胞、组织和发育阶段的特异性;多细胞生物中具有重要生理意义的自噬新蛋白质机器和新通路;自噬核心蛋白质机器的组装、蛋白质复合体的形成及多种蛋白质的翻译后修饰等高层调控体系;自噬晚期事件以及核心蛋白质机器;细胞面对不同的代谢胁迫条件会启动的不同的自噬通路等几个方面探讨自噬领域的研究方向和突破点,并讨论自噬领域研究的策略和方法。

Autophagy is an evolutionally conserved lysosome （vacuole）-dependent process, which degrades damaged or unwanted redundant cellular contents to generate biomolecules. The function of autophagy has been shown to be tightly related to human health and diseases. The Nobel Prize in Physiology or Medicine 2016 was awarded to Yoshinori Ohsumi ＂for his discoveries of mechanisms for autophagy＂. Current research on autophagy focus on Saccharomyces cerevisiae or essential protein machinaries identified from yeast genetic screenings. However, studies using single cell organisium yeast, or single induction conditions for autophagy have obvious limitations. In this review, we will propose several im- portant questions in the autophagy field. Multicellular organisms have differnet cells, tissue or developmental stages which certanly require new autophagy machinar- ies. This is an important directions for autophagy stud- ies, especially disease related studies. We should also pay more attention to the assembling mechanisums, the formation of protein complexes and posttranslational modifications of core machinary of autophagy. How the late stage of autophagy is regulated and the mechanism of lysosome biogenesis remains to be answered. Autophagy induced by multiple stimuli, for example energy de- pletion, is more related to physiology conditions and is the future directions of autophagy research. We will also discuss the strategies and technique development of autophagy studies.