探討 NudC 調控細胞自噬的分子機制

Abstract

細胞自噬 (Autophagy) 是真核生物體內一種降解受損胞器和物質的過程，透過細胞自噬可以維持細胞恆定並且可以透過回收降解物質幫助細胞度過逆境。在細胞自噬的過程中，受損的胞器與物質會被雙層膜構造的細胞自噬小體所包裹，細胞自噬小體會再和溶酶體融合形成自噬溶小體，接著所包裹的胞器與物質會被溶酶體帶來的酸性酵素所降解。核遷移蛋白C (NudC)已知在有絲分裂和細胞質分裂中扮演重要的角色，除此之外，已經有其他文獻發現NudC突變會降低細胞自噬小體和內噬體進行反向運輸時的速率，但對於NudC在細胞自噬中的功能仍不清楚。近來我們透過將果蠅以及哺乳類細胞中弱化NudC，發現在飢餓引發細胞自噬的狀況下會使Microtubule-associated proteins 1A/1B light chain 3A (LC3)的數量下降，也會妨礙細胞自噬的進行。此外也發現NudC是因不同刺激引發細胞自噬時的廣泛調控因子。另一方面，目前已知有一部分的WD重複結構域磷酸肌醇相互作用蛋白(WIPI)成員會和NudC有交互作用，我們發現當在細胞中弱化NudC時會使WIPI2的數量降低。我們還有在果蠅的不同組織中弱化NudC，發現眼睛會有縮小以及翅膀會有萎縮的表徵。未來我們將會進一部探討NudC詳細於細胞自噬中的功能，以及了解NudC對於WIPI 蛋白於細胞自噬中的影響。

Autophagy is a conserved process in eukaryotes by which the intracellular materials are degraded for recycling. Autophagy is important for maintaining cellular homeostasis and recycling cytosolic materials in response to various stress stimulation. During autophagy, the cargo is engulfed into double-membrane structures called autophagosomes, followed by fusing with lysosome to form autolysosomes. The cargo in autolysosomes then degraded by various acidic enzyme in lysosomes. Nuclear migration protein C (NudC) plays an essential role in mitosis and cytokinesis. Although NudC mutants have been implicated reducing the velocity of autophagosomes and late endosomes retrograde transport, the function of NudC in autophagy remains unclear. Recently, we observed that knockdown of NudC results in the reduction of LC3 puncta formation and impaired autophagic flux in both Drosophila larval fat bodies and mammalian cells under starvation conditions. Moreover, our results indicate that NudC is a general regulator of autophagy in reponse to various stresses stimulation. The WIPI members have been reported to interact with NudC. In this study, we found that the number of WIPI1 and WIPI2 decreased in NudC knockdown cells. Furthermore, we investigated the developmental function of NudC by crossing dNudC-RNAi with various drivers in Drosophila and found that dNudC knockdown cause small eye and aberrant wing phenotypes. In the future, we will investigate the molecular function of NudC in autophagy and explore the relationship between NudC and WIPI proteins in autophagy.