化膿性鏈球菌 (Streptococcus pyogenes)，又稱A群鏈球菌 (GAS)，是人類常見的傳染性致病菌，於臨床上也造成許多疾病，包括：非侵入性感染所造成的咽喉炎，以及侵入性感染所造成的壞死性筋膜炎和鏈球性毒性休克症候群。在過去的研究中A群鏈球菌普遍被認為是屬於細胞外感染的致病菌，但近年來的文獻顯示，A群鏈球菌可以侵入至宿主的非免疫細胞中感染，藉此逃脫宿主的免疫反應以及抗生素治療，促使A群鏈球菌可以在細胞內存活並且複製，進而造成嚴重的侵襲疾病。近期有許多文獻顯示，非免疫細胞是可以透過溶酶體所介導的異源吞噬來清除掉內源性的病原菌。此外，前人先前的研究結果表示，Galectin-8會黏附於內含A群鏈球菌的囊泡中，並招集Parkin聚集至囊泡處進行泛素化修飾，從而啟動異源吞噬，導致A群鏈球菌被清除。然而，Galectin-8/Parkin相互作用所引起的異源吞噬的分子機制至今仍然是未知的。因此，在本篇研究中，主要探討在A群鏈球菌感染之下Galectin-8/Parkin 是如何形成複合體 (complex)，以及此複合體是如何調控異源吞噬的機制。在實驗結果中，重組蛋白質Galectin-8和Parkin已被過度表現以及純化，並由大小排阻層析法 (size-exclusion chromatography) 證明此兩種蛋白質在體外 (in vitro) 並不直接相互作用，除此之外，也以酵母菌雙雜合系統 (yeast two-hybrid system)驗證Galectin-8和Parkin在體內 (in vivo) 也無物理上的接觸。最後以免疫共沈澱 (co-immunoprecipitation) 聯合液相層析質譜儀鑑定 (liquid chromatography-mass spectrometry) 於A群鏈球菌感染之下，與Galectin-8相互作用之蛋白質。根據我們結果得知，我們猜測Galectin-8和Parkin 在體內會形成多元複合體。因此，在未來的研究中，我們應鑑定其連接 Galectin-8和Parkin相關的蛋白質，並深入探討異源吞噬的詳細機制。最後，我們希望可以透過蛋白質結構為基礎，在未來能設計針對參與在異源吞噬中相關蛋白質的促進劑，藉此誘導異源吞噬，促進內源性A群鏈球菌的清除。

Group A Streptococcus (GAS) causes a variety of human clinical diseases ranging from noninvasive infections such as pharyngitis to severe invasive infections involving necrotizing fasciitis and streptococcal toxic shock syndrome. Although GAS has been considered to be an extracellular pathogen, recent studies found that the internalization of GAS into nonimmune cells provides a strategy for GAS to escape killing by host immune responses and antibiotics treatment. Nevertheless, nonimmune cells use xenophagy to eliminate intracellular pathogens by promoting lysosome-mediated degradation. Previous studies showed that Galectin-8 binds to GAS-containing vacuoles and recruits Parkin to adapt ubiquitin leading to xenophagy during GAS infection. However, the molecular mechanism underlying the Galectin-8/Parkin interactions that induce xenophagy is still unknown. Hence, we aim to elucidate the molecular basis of the Galectin-8/Parkin complex to understand how the complex is modulated in xenophagic machinery during intracellular GAS infection. The recombinant Galectin-8 and Parkin were overexpressed and purified. Furthermore, size-exclusion chromatographic analysis demonstrated that these two proteins do not interact directly in vitro. In addition, Galectin-8 does not physically associate with Parkin in vivo by yeast two-hybrid system. Additionally, the co-immunoprecipitation coupled with liquid chromatography-mass spectrometry was employed to investigate which protein(s) or molecule(s) associates with Galectin-8 during GAS infection. Based on our results, we suggest that Galectin-8 and Parkin might take part of a multicomponent complex in vivo. Therefore, future studies should be focused on identifying proteins associated with Galectin-8 or Parkin to form a multisubunit protein complex and to have a better understanding of the detailed mechanism of xenophagy. These researches may provide us insights into a future therapeutic design for promoting xenophagy to eliminate GAS infection.

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