Necroptosis-blocking compound NBC1 targets heat shock protein 70 to inhibit MLKL polymerization and necroptosis.

Proceedings of the National Academy of Sciences of the United States of America
Andrea N JohnstonZhigao Wang

Abstract

Necroptosis is a regulated necrotic cell death pathway involved in development and disease. Its signaling cascade results in the formation of disulfide bond-dependent amyloid-like polymers of mixed lineage kinase domain-like protein (MLKL), which mediate proinflammatory cell membrane disruption. We screened compound libraries provided by the National Cancer Institute and identified a small-molecule inhibitor of necroptosis named necroptosis-blocking compound 1 (NBC1). Biotin-labeled NBC1 specifically conjugates to heat shock protein Hsp70. NBC1 and PES-Cl, a known Hsp70 substrate-binding inhibitor, block the formation of MLKL polymers, but not MLKL tetramers in necroptosis-induced cells. In vitro, recombinant Hsp70 interacts with the N-terminal domain (NTD) of MLKL and promotes NTD polymerization, which has been shown to mediate the cell killing activity. Furthermore, the substrate-binding domain (SBD) of Hsp70 is sufficient to promote MLKL polymerization. NBC1 covalently conjugates cysteine 574 and cysteine 603 of the SBD to block its function. In addition, an SBD mutant with both cysteines mutated to serines loses its ability to promote MLKL polymerization. Interestingly, knockdown of Hsp70 in cells leads to MLKL destabilizat...Continue Reading

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Citations

Sep 19, 2020·Molecular & Cellular Oncology·Andrea N Johnston, Zhigao Wang
Jan 12, 2021·Free Radical Biology & Medicine·Sabira MohammedSathyaseelan S Deepa
Jan 20, 2021·Cell Death and Differentiation·Yanxiang MengJames M Murphy
May 1, 2021·Scientific Reports·Xiaodong SunMing Sang
Jun 3, 2021·Experimental & Molecular Medicine·Jinho SeoJaewhan Song
Sep 10, 2020·ACS Chemical Biology·Catia L PierottiGuillaume Lessene

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