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Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-?B signaling.


ABSTRACT: The NF-?B family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-?B has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-?B activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-?B activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO-IKK? interaction and was a poor direct IKK? inhibitor, but prevented the formation of TNF-induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMO(Y308S) mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo.

SUBMITTER: Jackson SS 

PROVIDER: S-EPMC4302062 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling.

Jackson Shawn S SS   Oberley Christopher C   Hooper Christopher P CP   Grindle Kreg K   Wuerzberger-Davis Shelly S   Wolff Jared J   McCool Kevin K   Rui Lixin L   Miyamoto Shigeki S  

Experimental cell research 20141007 1


The NF-κB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-κB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-κ  ...[more]

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