Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

Qing, Guoliang; Yan, Pengrong; Qu, Zhaoxia; Liu, Hudan; Xiao, Gutian

doi:10.1038/cr.2007.47

Cited by 99 publications

(94 citation statements)

References 36 publications

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“…Evidence exists that in this ER-positive and selective estrogen modulator (one of which is tamoxifen)-sensitive cell lines, NF-B signaling should be attributed to p50 and Bcl3 rather than to p65 (68,69). Another interesting work demonstrated that autophagy represents a new route for NF-B-inducing kinase degradation and negatively regulates alternative NF-B pathways (47). In light of these findings and of our data, it is tempting to speculate that autophagy, once acutely induced through a classical mode of NF-B activation, could terminate the whole NF-B pathway, working as a negative feedback mechanism.…”

Section: Discussionmentioning

confidence: 99%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

239

179

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Recently, autophagy has emerged as a critical process in the control of T-cell homeostasis. Given the pivotal role of NF-B in the signaling events of T cells, we have analyzed and unveiled a conserved NF-B binding site in the promoter of the murine and human BECN1 autophagic gene (Atg6). Accordingly, we demonstrate that the NF-B family member p65/RelA upregulates BECN1 mRNA and protein levels in different cellular systems. Moreover, p65-mediated upregulation of BECN1 is coupled to increased autophagy. The newly identified B site in the BECN1 promoter specifically interacts with p65 both in vitro and in living Jurkat cells upon phorbol myristate acetate (PMA)-ionomycin stimulation, where p65 induction is coupled to BECN1 upregulation and autophagy induction. Finally, anti-CD3-and PMA-ionomycin-mediated activation of T-cell receptor signaling in peripheral T cells from lymph nodes of healthy mice results in an upregulation of BECN1 expression that can be blocked by the NF-B inhibitor BAY 11-7082. Altogether, these data suggest that autophagy could represent a novel route modulated by p65 to regulate cell survival and control T-cell homeostasis.Normal cellular development and growth depend on a finely tuned balance between protein synthesis and degradation. Eukaryotic cells exploit two major routes for protein degradation: autophagy and the ubiquitin-proteasome system. Autophagy is a highly conserved catabolic process whereby long-lived proteins and organelles are engulfed in double-membrane structures called autophagosomes and targeted to the lysosome for degradation and ATP production (33). Autophagy was first characterized in yeast as a process used by cells to survive metabolic stress (59). Many of the autophagic executor genes (ATGs) have been discovered in yeast, and recently a number of mammalian orthologues have been identified. At the molecular level, the autophagic pathway is well conserved and requires several proteins acting in concert at different stages for proper autophagosome formation. During the first steps of autophagosome formation, BECN1/Atg6 acts in association with PI3KIII/Vps34 as a platform that recruits activators and inhibitors of autophagy in order to finely regulate autophagosome formation (43). Two ubiquitin-like systems are fundamental for autophagosome enlargement and maturation downstream of BECN1. A first ubiquitin-like system is required for the formation of the Atg5-Atg12 complex, which contributes to autophagosomal membrane elongation (30, 39). The second ubiquitin-like system conjugates LC3 protein to phosphoethanolamine, allowing its incorporation into the autophagosomal membrane and subsequent autophagosome formation (56).In mammalian cells, metabolic stress and genotoxic stimuli, including ceramide and tamoxifen treatment, have been shown to trigger both apoptotic cell death and autophagy (51). A number of emerging pieces of evidence point to a prosurvival role for autophagy. Inactivation of the essential autophagy gene BECN1 results in apoptotic cell death in different mode...

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Section: Discussionmentioning

confidence: 99%

p65/RelA Modulates BECN1 Transcription and Autophagy

Copetti

Bertoli

Dalla

et al. 2009

Molecular and Cellular Biology

239

179

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“…Conversely, autophagic process has a negative impact on the activation of IKK and NF-B. For instance, autophagy facilitates the degradation of the IKK complex and its upstream activator NF-Binducing kinase, contributing to the inhibition of NF-B signaling (47). Furthermore, autophagic process depletes p62 (sequestosome1), an activator of the IKK complex, resulting in a diminished activity of NF-B (48).…”

Section: Discussionmentioning

confidence: 99%

HTLV-2 Tax Immortalizes Human CD4+ Memory T Lymphocytes by Oncogenic Activation and Dysregulation of Autophagy

Ren

Dong

Takahashi

et al. 2012

Journal of Biological Chemistry

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Background: Human T cell leukemia virus type 2 (HTLV-2) encodes a viral transactivator Tax. Results: HTLV-2 Tax efficiently immortalizes human memory T lymphocytes with distinct T cell subtypes. Conclusion: HTLV-2 Tax connects IB kinase complex to autophagy pathways for promoting T cell survival and proliferation. Significance: Learning the oncogenic potential of HTLV-2 Tax is critical for understanding HTLV-2 pathogenesis.

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“…35 In most cancer cells, the hyperactivation of HSP90 stabilizes its client proteins and protects from stress; the specific inhibition of HSP90 by some chemicals can lead to the degradation of its clients via autophagy. 36,37 In leukemic cells, sodium selenite decreased HSP90 expression and attenuated its interaction with the protein inhibitor of nuclear factor κB, finally resulting in the cell-signaling switch from autophagy to apoptosis. 9 Herein, we proved that HSP90 sequestered by SeNPs is the real cause of HSP90 decreases, therefore revealing the link between autophagy inhibition and HSP90 decrease in selenite-treated cancer cells.…”

Section: Endogenous Senps-inhibited Autophagymentioning

confidence: 99%

Selenite-Induced Toxicity in Cancer Cells Is Mediated by Metabolic Generation of Endogenous Selenium Nanoparticles

et al. 2015

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Selenite has been a touted cancer chemopreventative agent but generates conflicting outcomes. Multiple mechanisms of selenite cytotoxicity in cancer cells are thought to be induced by metabolites of selenite. We observed that intracellular metabolism of selenite generates endogenous selenium nanoparticles (SeNPs) in cancer cells. Critical proteins that bind with high affinity to elemental selenium during SeNPs self-assembly were identified through proteomics analysis; these include glycolytic enzymes, insoluble tubulin, and heat shock proteins 90 (HSP90). Sequestration of glycolytic enzymes by SeNPs dramatically inhibits ATP generation, which leads to functional and structural disruption of mitochondria. Transcriptome sequencing showed tremendous down-regulation of mitochondrial respiratory NADH dehydrogenase (complex I), cytochrome c oxidase (complex IV), and ATP synthase (complex V) in response to glycolysis-dependent mitochondrial dysfunction. Sequestration of insoluble tubulin led to microtubule depolymerization, altering microtubule dynamics. HSP90 sequestration led to degradation of its downstream effectors via autophagy, ultimately resulting in a cell-signaling switch to apoptosis. Additionally, the surface effects of SeNPs generated oxidative stress, thus contributing to selenite cytotoxicity. Herein, we reveal that the multiple mechanisms of selenite-induced cytotoxicity are caused by endogenous protein-assisted self-assembly of SeNPs and suggest that endogenous SeNPs could potentially be the primary cause of selenite-induced cytotoxicity.

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Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

Cited by 99 publications

References 36 publications

p65/RelA Modulates BECN1 Transcription and Autophagy

p65/RelA Modulates BECN1 Transcription and Autophagy

HTLV-2 Tax Immortalizes Human CD4+ Memory T Lymphocytes by Oncogenic Activation and Dysregulation of Autophagy

Selenite-Induced Toxicity in Cancer Cells Is Mediated by Metabolic Generation of Endogenous Selenium Nanoparticles

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