Journal
CELL CHEMICAL BIOLOGY
Volume 23, Issue 2, Pages 257-266Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2015.08.018
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Funding
- National Basic Science 973 grants from the Chinese Ministry of Science and Technology [2013CB530805, 2015CB856200]
- National Natural Science Foundation of China (NNSFC) [21561142002, 21472010, 91313303, 81571385]
- Beijing Nova Program grant from the Beijing Municipal Commission of Science and Technology [xx2012070/Z121102002512077]
- Special Research Foundation of State Key Laboratory of Medical Genomics
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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.
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