NIK is required for NF-κB-mediated induction of BAG3 upon inhibition of constitutive protein degradation pathways

Cell Death & Disease
F RapinoSimone Fulda

Abstract

Recently, we reported that induction of the co-chaperone Bcl-2-associated athanogene 3 (BAG3) is critical for recovery of rhabdomyosarcoma (RMS) cells after proteotoxic stress upon inhibition of the two constitutive protein degradation pathways, that is, the ubiquitin-proteasome system by Bortezomib and the aggresome-autophagy system by histone deacetylase 6 (HDAC6) inhibitor ST80. In the present study, we investigated the molecular mechanisms mediating BAG3 induction under these conditions. Here, we identify nuclear factor-kappa B (NF-κB)-inducing kinase (NIK) as a key mediator of ST80/Bortezomib-stimulated NF-κB activation and transcriptional upregulation of BAG3. ST80/Bortezomib cotreatment upregulates mRNA and protein expression of NIK, which is accompanied by an initial increase in histone H3 acetylation. Importantly, NIK silencing by siRNA abolishes NF-κB activation and BAG3 induction by ST80/Bortezomib. Furthermore, ST80/Bortezomib cotreatment stimulates NF-κB transcriptional activity and upregulates NF-κB target genes. Genetic inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) or by knockdown of p65 blocks the ST80/Bortezomib-stimulated upregulation of BAG3 mRNA and protein expressi...Continue Reading

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Citations

May 11, 2016·Trends in Pharmacological Sciences·Christian Behl
May 2, 2017·Annual Review of Biochemistry·Ivan Dikic
Aug 16, 2017·Journal of Cell Science·Christina KlimekJörg Höhfeld
Jul 7, 2017·Frontiers in Molecular Neuroscience·Elisabeth Stürner, Christian Behl
Nov 8, 2020·Cells·Christof HiebelChristian Behl
Apr 13, 2021·Frontiers in Physiology·Qianghua XiaYongjie Wei

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Methods Mentioned

BETA
ubiquitination
histone acetylation
acetylation
ChIP
transfection
fluorescence-activated cell-sorting
flow cytometry
reverse transcription PCR

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