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  • 學位論文

泛素接合酶ZNRF1藉由影響caveolin-1之代謝影響第四型類鐸受體驅動之免疫反應

The Ubiquitin Ligase ZNRF1 Promotes Caveolin-1 Ubiquitination and Degradation to Modulate TLR4-driven Immune Response

指導教授 : 徐立中
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摘要


泛素接合酶(ubiquitin E3 ligase)是一種蛋白酵素,它可以辨認並催化特定蛋白與泛素(ubiquitin)進行共價鍵結。泛素鍵結作用調控了許多各種不同的重要細胞功能,包括細胞週期的控制、細胞內蛋白質運送、DNA修復、以及細胞內訊息傳導。在這篇研究裡面,主旨在研究泛素接合酶對於第四型類鐸受體(Toll-like receptor 4)訊息調控的影響。我們發現有一個泛素接合酶ZNRF1可以藉由影響另一個蛋白質caveolin-1 (CAV1)來調控第四型類鐸受體受到刺激之後產生的免疫反應。我們也發現了ZNRF1與CAV1會有接觸與作用,在細胞受到脂多糖(lipopolysaccharide)的刺激後,ZNRF1會催化CAV1接受泛素鍵結並促使CAV1在細胞內分解。CAV1在細胞內是細胞小凹(caveolae)主要的組成蛋白並調控許多細胞生理功能以及變化,例如發炎反應以及癌細胞的生長。目前已之泛素鍵結作用可以影響CAV1在細胞內表現量的變化。我們的研究同時也發現ZNRF1與CAV1在第四型類鐸受體受到活化之後,會調控Akt與GSK3b的功能來增加促進發炎反應細胞激素的分泌並且減少抑制發炎反應細胞激素的分泌。剔除ZNRF1基因的基因轉殖小鼠可以減少發炎反應並且剔除ZNRF1基因的基因轉殖小鼠對於內毒素(endotoxin)或是敗血症引起的休克有比較高的抵抗力以及存活率。我們的研究發現ZNRF1這個蛋白對於第四型類鐸受體引起的發炎反應是一個新的調控蛋白質,我們也發現了一個新的調控機制透過CAV1來影響第四型類鐸受體引起的發炎反應。

關鍵字

ZNRF1 caveolin-1 TLR4 第四型類鐸受體

並列摘要


Ubiquitination catalyzed by E3 ligases are important enzymes in cell biology and regulate diverse cellular functions such as cell cycle control, protein trafficking, DNA repair, and signaling. Many E3 ubiquitin ligases have been characterized as important immune regulators. To characterize the molecular mechanisms underlying the immunoregulatory functions of these E3 ligases in physiologically relevant immune cells is still a challenge. Our research found that E3 ubiquitin ligase ZNRF1 modulates caveolin-1 (CAV1) protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. We demonstrate that ZNRF1 interacts with CAV1 in response to lipopolysaccharides and mediates its ubiquitination and degradation. CAV1, the major constituent of caveolae, plays a pivotal role in various cellular physiological and pathological processes. The ubiquitin pathway is known to regulate the level of CAV1 in cells. Our research also found that ZNRF1-CAV1 axis regulates Akt-GSK3b activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine. Znrf1-deficient mice are more resistant to endotoxic and polymicrobial septic shock due to attenuated inflammation. Our study has identified ZNRF1 as a new regulator of TLR4-induced inflammatory responses and revealed a novel mechanism for the regulation of TLR4 signaling through CAV1.

並列關鍵字

ZNRF1 caveolin-1 TLR4

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