SIK2 對細胞自噬的調控

Abstract

本文主要探討 SIK2 在細胞自噬中扮演的功能。SIK2 為 AMPK 家族的一員，目前已知參與於脂肪細胞的分化和胰島素訊號傳導的調控。SIK2 的其他功能目前尚待研究。先前我們實驗室發現 SIK2 藉由和 p97/VCP 之交互作用而調控 ER-associated protein degradation (ERAD)，也發現 SIK2 可能參與調控蛋白質聚集體的降解。在本篇研究，進一步證實SIK2 可能參與調控細胞自噬。當使用 MG132 來誘導包涵體和聚集體的形成時,發現 SIK2 和 p62 或是 HDAC6 之間有交互作用或複合體之存在。當細胞表現正常激酶活性的 SIK2 時，會導致泛素化蛋白質和 LC3-II 減少，顯示SIK2 極有可能參與處理蛋白質聚集體,且SIK2 可能透過和 p97/VCP 之交互作用並和 p62 、HDAC6 或是 Hsp90複合體之形成達到蛋白質聚集體的降解。另外，在蛋白質分泌的實驗中發現， SIK2 亦可能藉由調控細胞胞器而影響了蛋白質的分泌。本論文之結果顯示: SIK2不但在蛋白質聚集體的降解扮演主要調控功能它也極可能在ERAD和細胞自噬之間扮演協調者之角色。

SIK2 (salt-inducible kinase 2) belongs to members of AMPK family. Other than the regulation of adipocyte differentiation and insulin signal transduction, the functions of SIK2 remain largely unknown. Previously, we showed that SIK2 can interact with p97/VCP to regulate ER-associated protein degradation (ERAD). SIK2 may also involve in inclusion body or aggresome processing. In this study, I investigate how SIK2 is involved in regulation of autophagy. SIK2 could be found in complex containing either p62/SQSTM1 or HDAC6 when the cells are treated with proteosome inhibitor MG132. Overexpression of WT-SIK2 resulted in decrease of ubiquitinated proteins and LC3-II levels. SIK2 may facilitate aggresome processing through p62, HDAC6 or Hsp90. In a ligand-induced protein secretion system using human growth hormone as reporter indicates that SIK2 plays crucial roles in autophagy-mediated protein secretion. My study demonstrated that SIK2 could serve as a positive regulator in autophagic-mediated protein degradation and secretion. Together these results suggest that SIK2 may function as a coordinator for the ER stress response and autophagy.