Cited by 136Cell death mechanisms and regulationHeat shock proteins researchNF-κB Signaling Pathways

Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis

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Zhao, X M, Chen, Z, Zhao, J B, Zhang, P P, Pu, Y F, Jiang, S H, Hou, J J, Cui, Y M +2 more·2016·Cell Death & Disease

Abstract

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIP3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIP3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.

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Authors
Zhao, X. M., Chen, Z., Zhao, J. B., Zhang, P. P., Pu, Y. F., Jiang, S. H., Hou, J. J., Cui, Y. M., Jia, X. L., & Zhang, S. Q.
Affiliations
Xiamen University (CN)
Corresponding author
Zhang, S Q
Venue
Cell Death & Disease
Published
2016-02-11
Volume
7
Issue
2
Pages
e2089-e2089
ISSN
2041-4889 (ISSN-L)
OpenAlex
W2418456889
Cited by
135
References
31
Citations by year
2026: 7 · 2025: 13 · 2024: 13 · 2023: 15 · 2022: 16 · 2021: 20 · 2020: 18 · 2019: 11 · 2018: 7 · 2017: 7 · 2016: 8
FWCI
5.71
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (B06016, 111 Project, 31271479, B12001, 31471298)
  • Xiamen University
  • Higher Education Discipline Innovation Project (B12001)
  • Project 211 (B06016, 111 Project, B12001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
HSP90, MLKL, necroptosis, TNF signaling, protein stability, proteasomal degradation, 17-AAG, MLKL phosphorylation, plasma membrane translocation, molecular chaperones, protein-protein interaction
MeSH terms
Enzyme Stability, Humans, Necrosis, Phosphorylation, Protein Kinases, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, Apoptosis, HSP90 Heat-Shock Proteins, HEK293 Cells

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