Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis
Dianrong Li#, Chao Li#, Lin Li, She Chen, Lei Wang, Qiang Li, Xiaodong Wang, Xiaoguang Lei* and Zhirong Shen*
Cell Chemical Biology 2016, 23, 257-266
Highlights ?Kongensin A (KA) is a potent inhibitor of necroptosis and an inducer of apoptosis ?KA inhibits necroptosis by preventing the activation of RIPK3 ?TQ ligation enables the identification of HSP90 as a cellular target of KA ?KA covalently binds to HSP90 and inhibits HSP90 through a novel mode of action Summary RIP3-dependent necroptosis […]
Highlights
?KA inhibits necroptosis by preventing the activation of RIPK3
?TQ ligation enables the identification of HSP90 as a cellular target of KA
?KA covalently binds to HSP90 and inhibits HSP90 through a novel mode of action
Summary
RIP3-dependent necroptosis has recently garnered significant interest because of the unique signaling mechanisms and pathologic functions involved in this process. Accordingly, a number of chemical screens have identified several effective small-molecule inhibitors that specifically block necroptosis. Here, we report the discovery that kongensin A (KA), a natural product isolated from?Croton kongensis, is a potent inhibitor of necroptosis and an inducer of apoptosis. Using a new bioorthogonal ligation method (TQ ligation), we reveal that the direct cellular target of KA is heat shock protein 90 (HSP90). Further studies demonstrate that KA covalently binds to a previously uncharacterized cysteine 420 in the middle domain of HSP90 and dissociates HSP90 from its cochaperone CDC37, which leads to inhibition of RIP3-dependent necroptosis and promotion of apoptosis in multiple cancer cell lines. Collectively, our findings demonstrate that KA is an effective HSP90 inhibitor that has potential anti-necroptosis and anti-inflammation applications.
http://www.cell.com/ccbio/abstract/S2451-9456(16)00027-1
