Dr Li Min (centre), Dr Lu Jiahong (right) and the research team


李敏博士 (中)、路嘉宏博士 (右) 與研究團隊

Date: 16 Jun 2014 (Monday)

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Collaborative autophagy research by Dr Li Min of School of Chinese Medicine published in Nature Communications

中醫藥學院李敏博士「自噬研究」合作論文獲刊載於著名科研雜誌《Nature Communications》

A joint research project entitled “NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity” by Dr Li Min, Associate Professor of the School of Chinese Medicine (SCM), and Professor Yue Zhenyu of the Department of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, USA, elaborates on the role of NRBF2 in autophagy regulation and liver injury prevention, and provides a novel drug target for autophagy modulation and liver injury prevention. The research article was published online in premier scientific journal Nature Communications in May (http://www.nature.com/ncomms/2014/140522/ncomms4920/full/ncomms4920.html).
 
Autophagy is a lysosome degradation pathway for material and energy recycling, and plays vital roles in the growth, development and homeostasis of cells. Dysregulation of autophagy has been linked to a number of diseases, including cancers and neurodegenerative diseases.
 
According to the findings of the research team, NRBF2 is a Beclin1-interaction protein and is a novel component of Beclin1-Vps34 complex which contributes to the regulation of cell autophagy. To explore the physiological function of NRBF2, the research team created NRBF2 knockout mice. They have discovered that though knockout mice could survive, they suffered from liver injury and displayed accumulation of autophagy substrate. The study further revealed that NRBF2 played an important role in modulating autophagy and Atg14L-linked Vps34 kinase activity, and demonstrated that NRBF2 worked as an adaptor to promote the assembly of Beclin1-Atg14L complex and Vps34-Vps15 complex for regulation of autophagy, Vps34 kinase activity as well as liver injury. Interestingly, the NRBF2 KO cells displayed increased sensitivity to endoplasmic reticulum stress, indicating the function of NRBF2 in preventing ER stress-associated cell death. 
 
Dr Li Min said that the study uncovers the physiological function of NRBF2 and provides a novel therapeutic target for autophagy-associated liver damage and ER stress-associated disorders including neurodegenerative diseases and cancers, which could lead to the discovery of innovative therapy and drugs for those diseases.
 
The co-principal author of the article, Dr Lu Jiahong, is a postdoctoral fellow jointly nurtured by SCM and Icahn School of Medicine at Mount Sinai. His research focuses are the regulation mechanism of autophagy and small molecular Chinese medicinal compounds as natural autophagy enhancers.

中醫藥學院副教授李敏博士與美國西奈山伊坎醫學院神經科學系教授岳振宇教授的一項聯合研究,題為「NRBF2通過調節Atg14L結合的磷脂醯肌醇激酶活性調控自噬和防止肝臟損傷」,闡明了NRBF2蛋白在細胞自噬調控和防止肝臟損傷中的作用機制,為自噬調控和肝臟損傷治療提供了新的藥物靶點。有關研究論文於5月在國際著名科研雜誌《Nature Communications》的網上版發表(http://www.nature.com/ncomms/2014/140522/ncomms4920/full/ncomms4920.html)。
 
「自噬」是細胞通過溶酶體機制自我消化進行物質能量循環的過程,也是調控細胞生長、發育與穩態的重要機制,有助細胞產物在合成、降解及循環中保持一個平衡狀態。它與多種人類疾病,如腫瘤和神經退行性疾病有密切關係。
 
研究小組發現NRBF2是一個與Beclin1 相互作用的蛋白,是Beclin1-Vps34磷脂激酶複合物的重要成分,有助調控細胞自噬。為了探索NRBF2 的生理功能,研究小組以小鼠作為實驗動物,通過基因改造令小鼠喪失NRBF2 基因的功能。實驗結果顯示,喪失了NRBF2 基因的小鼠雖然能夠正常存活,但小鼠的肝臟出現了明顯的損傷和堆積了大量的自噬底物。此外,研究亦進一步發現,NRBF2 有重要的調節功能及類似於橋樑的作用,連結了Beclin1-Atg14L蛋白複合物和Vps34-Vps15蛋白複合物,從而確保自噬和磷脂醯肌醇激酶活性正常,防止出現與自噬相關的肝臟損傷。有趣的是,喪失了NRBF2 基因的細胞表現出對內質網應激(一種細胞應激反應,在腫瘤和神經退行性疾病中會被異常啟動)的敏感性,提示該蛋白能緩解內質網應激相關的損傷。
 
李敏博士表示,研究結果揭示了NRBF2 的生理功能,也為自噬調控、肝臟損傷和內質網應激損傷的相關疾病,如腫瘤和神經系統退行性疾病,提供了新的調控機制和治療靶點,有助於研究人員針對上述人類頑疾尋找新的治療方法及研發新藥。
 
該論文的共同第一作者路嘉宏博士是浸大中醫藥學院和西奈山伊坎醫學院聯合培養的博士後研究員,他在西奈山伊坎醫學院的主要研究方向是細胞自噬的調控機制和中藥小分子自噬調控劑的藥理作用。