【原】抑癌因子folliculin抑制乳酸脱氢酶A，调节Warburg效应

 The tumor suppressor folliculin inhibits lactate  dehydrogenase A and regulates the Warburg effect

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|核心内容：

癌细胞中的有氧糖酵解，也被称为“Warburg效应”，是由乳酸脱氢酶A(LDHA)的过度活跃驱动的。

LDHA被认为是一种底物调节酶，但目前尚不清楚是否有一种专门的细胞内蛋白也调节其活性。

在这里，我们鉴定了人类肿瘤抑制剂滤泡素(FLCN)作为LDHA的结合伙伴和非竞争性抑制剂。

FLCN氨基末端的一个灵活的环控制着LDHA活性位点环的运动，严格调节其酶活性，从而控制正常细胞的代谢稳态。

经历Warburg效应的癌细胞显示FLCN与LDHA分离。

用来自FLCN环区的十肽处理这些细胞会导致细胞死亡。

我们的数据表明，癌细胞的糖酵解转移是FLCN失活或从LDHA解离的结果。

总之，FLCN介导的LDHA抑制为糖酵解的调控提供了一个新的范例。

In normal cells, FLCN regulates  the activity of LDHA.  In cancer cells experiencing the Warburg effect, FLCN  and LDHA have lost the ability to interact, leading to the hyperactivity of  LDHA.

原文摘要：

 Aerobic glycolysis in cancer cells, also known as the 'Warburg effect’, is driven by hyperactivity of lactate dehydrogenase  A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein  also regulates its activity. 

Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site  loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the  FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. 

Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation  of glycolysis.

FLCN-FLAG IP from HEK293 cells was subjected to matrix-assisted laser  desorption/ionization–time-of-flight (MALDITOF) analysis. Colored circles  are interacting proteins: green, chaperones and adaptors; red, transcription,  translation and metabolism; blue, nucleotide-binding; cyan, RNA-binding;  beige, chaperonins and cytoskeleton. The interactome was generated using  STRING () https:///cgi/input?sessionId=bmbx2TGQFt9V&input_page_show_search=on

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参考文献：https://www./articles/s41594-021-00633-2

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