Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis
Open accessAbstract
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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HSP90 has specific and non-redundant role in MLKL oligomerization and translocation.
“Recent studies ascribe to the heat shock protein 90 kDa alpha family class A member 1 (HSP90AA1; best known as HSP90) a specific and non-redundant role in MLKL oligomerization and translocation [454, 455].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [454]
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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)
- PMC
- PMC4849146
- 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
- gold
- doi.org
- 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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