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

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.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Zhao XM,Chen Z,Zhao JB,Zhang PP,Pu YF,Jiang SH,Hou JJ,Cui YM,Jia XL,Zhang SQ

doi

10.1038/cddis.2015.390

subject

Has Abstract

pub_date

2016-02-11 00:00:00

pages

e2089

issn

2041-4889

pii

cddis2015390

journal_volume

7

pub_type

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