果蠅去泛素酶Leon調控細胞自噬之研究

Abstract

細胞自噬是細胞遇到惡劣環境時會啟動的一種分解性機制，利用數種的ATG蛋白質形成雙層膜構造分解不需要或受破壞的胞器，用以維持細胞恆定。泛素化作用為被用來調控要被代謝物質的重要機制，部分泛素連接酶 (E3 ligase)如Traf6和Parkin被發現與細胞自噬有關，而它的逆反應去泛素化也扮演重要的角色。在人體中的去泛素酶 (deubiquitinating enzyme)有超過90種，根據其催化域可分為5大類: USP, UCH, MJD, OUT,JAMM。過去許多報導發現去泛素酶會參與調控細胞自噬，像是USP36在果蠅中會調控選擇性自胞自噬的活化，USP30和Parkin互為結抗調控粒線體自噬。此外，我們發現果蠅中的Leon被抑制後會有細胞自噬體的累積，同時細胞自噬的受質P62也有累積的現象，另外用同時帶有紅色和綠色螢光的Atg8a也發現在Leon抑制的情況下有紅色和同時帶有紅色和綠色的Atg8a累積，說明Leon可能參與調控細胞自噬。我們將進一部探討Leon如何調控細胞自噬的分子機制。

Autophagy is a catabolic process for cell survival under stress conditions. Autophagy related proteins (Atgs) regulate autophagosome formation to degrade damaged organelles or aggregate proteins for maintaining cellular homeostasis. Ubiquitination is an important mechanism to modulate protein degradation. Several E3 ligases such as Traf6 and Parkin have been found to be involved in autophagy. Because ubiquitination is reversible, deubiquitination may play an important role in autophagy regulation. There are over 90 deubiquitinating enzyme (DUBs) in the human. According to their catalytic domain, DUBs can be divided to five classes: USP, UCH, MJD, OUT, JAMM. Previous studies showed that several DUBs involve in autophagy regulation. For example, USP36 regulates activity of selective autophagy.USP30 antagonizes mitophagy driven by the ubiquitin ligase Parkin. Here, we found that knockdown of the Drosophila DUB, Leon, causes autophagic structure and p62 accumulation. Moreover, Leon genetically and biochemically interacts with autophagy related protein. The molecular function of Leon in autophagy is further characterized.