近日,，中科院上海藥物所俞強(qiáng)課題組和上海有機(jī)所馬大為實(shí)驗(yàn)室在Journal of Cell Biology（JCB）上聯(lián)合發(fā)表了題為Cyclodepsipeptide toxin promotes the degradation of HSP90 client proteins through chaperone-mediated autophagy的論文。
該雜志為這篇論文專門撰寫了評(píng)述,。評(píng)述稱：這篇文章論述了兩個(gè)重要的發(fā)現(xiàn),。第一是發(fā)現(xiàn)了海洋藍(lán)藻環(huán)縮肽類毒素Apratoxin A抗腫瘤活性的分子機(jī)理，發(fā)現(xiàn)了其靶點(diǎn)為熱休克Hsp70/Hsc70家族蛋白,，為開發(fā)基于Apratoxin A的新一類抗腫瘤藥物奠定了理論基礎(chǔ),；第二是發(fā)現(xiàn)了細(xì)胞膜受體蛋白如EGFR能夠通過chaperone-mediated autophagy (CMA)途徑被降解。論文揭示Apratoxin A作用于Hsp70/Hsc70后促進(jìn)Hsp70/Hsc70與HSP90客戶蛋白的結(jié)合并經(jīng)CMA自噬途徑降解,。這在細(xì)胞生物學(xué)上是一個(gè)重要的新發(fā)現(xiàn),。先前該領(lǐng)域的研究一直認(rèn)為CMA自噬途徑只是用來降解胞質(zhì)內(nèi)蛋白,，而膜蛋白都是通過蛋白酶體（proteasome）途徑來降解。這一發(fā)現(xiàn)為細(xì)胞自噬這個(gè)當(dāng)前熱門研究領(lǐng)域做出了新貢獻(xiàn),，同時(shí)也使科學(xué)界對(duì)EGFR等重要膜受體蛋白的調(diào)控機(jī)理有了更深刻和全面的了解,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
