近日，中科院上海药物所俞强课题组和上海有机所马大为实验室在Journal of Cell Biology（JCB）上联合发表了题为Cyclodepsipeptide toxin promotes the degradation of HSP90 client proteins through chaperone-mediated autophagy的论文。
该杂志为这篇论文专门撰写了评述。评述称：这篇文章论述了两个重要的发现。第一是发现了海洋蓝藻环缩肽类毒素Apratoxin A抗肿瘤活性的分子机理，发现了其靶点为热休克Hsp70/Hsc70家族蛋白，为开发基于Apratoxin A的新一类抗肿瘤药物奠定了理论基础；第二是发现了细胞膜受体蛋白如EGFR能够通过chaperone-mediated autophagy (CMA)途径被降解。论文揭示Apratoxin A作用于Hsp70/Hsc70后促进Hsp70/Hsc70与HSP90客户蛋白的结合并经CMA自噬途径降解。这在细胞生物学上是一个重要的新发现。先前该领域的研究一直认为CMA自噬途径只是用来降解胞质内蛋白，而膜蛋白都是通过蛋白酶体（proteasome）途径来降解。这一发现为细胞自噬这个当前热门研究领域做出了新贡献，同时也使科学界对EGFR等重要膜受体蛋白的调控机理有了更深刻和全面的了解。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Cell Biology, Vol. 185, No. 4, 629-639 doi:10.1083/jcb.200810183
Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy
Shensi Shen1, Pengtao Zhang2, Martin A. Lovchik2, Ying Li2, Liuya Tang3, Zhimin Chen1, Rong Zeng3, Dawei Ma2, Junying Yuan4, and Qiang Yu1
1 Shanghai Institute of Materia Medica, 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, and 3 Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institue of Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
Promoting the degradation of Hsp90 client proteins by inhibiting Hsp90, an important protein chaperone, has been shown to be a promising new anticancer strategy. In this study, we show that an oxazoline analogue of apratoxin A (oz-apraA), a cyclodepsipeptide isolated from a marine cyanobacterium, promotes the degradation of Hsp90 clients through chaperone-mediated autophagy (CMA). We identify a KFERQ-like motif as a conserved pentapeptide sequence in the kinase domain of epidermal growth factor receptor (EGFR) necessary for recognition as a CMA substrate. Mutation of this motif prevents EGFR degradation by CMA and promotes the degradation of EGFR through the proteasomal pathway in oz-apraA–treated cells. Oz-apraA binds to Hsc70/Hsp70. We propose that apratoxin A inhibits Hsp90 function by stabilizing the interaction of Hsp90 client proteins with Hsc70/Hsp70 and thus prevents their interactions with Hsp90. Our study provides the first examples for the ability of CMA to mediate degradation of membrane receptors and cross talks of CMA and proteasomal degradation mechanisms.
