Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Yin, Shasha; Cao, Wangsen

doi:10.1128/mcb.00105-15

Cited by 81 publications

(61 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activated Nrf2 can be phosphorylated by GSK3β, which facilitates binding by β-TrCP and targeting for proteasomal degradation. Keap1 is degraded by autophagy, and can also bind and degrade IKK via autophagy.Activation of toll-like receptors (TLR), well known to induce an NF-κB-dependent inflammatory response, has recently been shown to activate Nrf2 via autophagy-dependent degradation of Keap1 [54]. Another NF-κB activating protein, Rho family GTP-binding protein (RAC1) [55,56], has recently been shown to also activate Nrf2, which subsequently blocks RAC1-dependent NF-κB activation [57].…”

mentioning

confidence: 99%

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Liddell¹

2017

J Clin Cell Immunol

View full text Add to dashboard Cite

Many neurodegenerative conditions involve redox imbalance and neuroinflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) are key transcription factors regulating antioxidant and inflammatory pathways, respectively. These two opposing factors are inversely regulated, with activity of one most often accompanied by diminished activity of the other, giving rise to the oxidative stress and neuroinflammation evident in neurodegeneration. Emerging evidence is uncovering a complex interplay between Nrf2 and NF-κB, involving extensive interaction of regulatory mechanisms including cytosolic activators and repressors, transactivation partners and direct transcriptional crosstalk. Understanding these interactions may provide insight into the pathophysiology of neuroinflammatory diseases and facilitate discovery of novel therapeutic targets. Keywords Nrf2 Function and ActivationNrf2 is the master regulator of antioxidant pathways, responsible for promoting the transcription of hundreds of antioxidant and cytoprotective genes, and in the brain appears to be repressed in neurons and predominantly restricted to glia [1,2]. Nrf2 is a cap'n' collar basic leucine zipper transcription factor. Under normal conditions, Nrf2 is bound in the cytosol by its negative regulator Kelch-like ECHassociated protein (Keap1), a substrate adaptor protein of a Cullin3-dependent ubiquitin E3 ligase complex. Keap1 constitutively targets Nrf2 for proteasomal degradation. When activated, Nrf2 dissociates from Keap1 and can translocate to the nucleus where it forms heterodimers with small Maf proteins and binds to antioxidant response elements (AREs), promoting the transcription of a battery of antioxidant and cytoprotective genes [3]. Nrf2 targets include genes for glutathione synthesis and utilization (e.g. GCLM, GCLC, GSTs), the thioredoxin and peroxiredoxin systems, NAPDH generation, iron metabolism (HMOX1, FTL, FTH) and quinone detoxification (NQO1) [4]. Nrf2 can be activated in response to oxidative stress and electrophiles via Keap1. Keap1 contains several highly sensitive cysteine residues that when oxidised cause Nrf2 to dissociate from Keap1, allowing Nrf2 to translocate to the nucleus. Thus Keap1 acts as a redox sensor [3]. Nrf2 activity is also regulated by kinases such as GSK3β [5]. Regulation of NF-κB ActivationNF-κB is a key regulator of the cellular inflammatory profile, promoting the transcription of inflammatory genes. In the brain, NF-κB signalling occurs predominantly in microglia, as well as astrocytes and oligodendrocytes, but not in neurons [6]. The NF-κB complex consists of homo-or heterodimers of p65, RelB, c-Rel, p50 and p52, the most abundant of which is p65/p50. The dimers are bound in the cytosol by a family of repressor proteins called inhibitor of κB (IκB), which include IκBα, IκBβ, IκBε, IκBγ and Bcl-3. IκB is phosphorylated by the IκB kinase (IKK) complex, consisting of IKKα, IKKβ and IKKγ subunits [7]. Upon activation by stimuli including TNFα, LPS and IL-1, IKK phosph...

show abstract

mentioning

confidence: 99%

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Liddell¹

2017

J Clin Cell Immunol

View full text Add to dashboard Cite

show abstract

“…LPS and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor [62]. The effect of activated Nrf2 on CYP genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54 , and Cyp2g1 increased, and Cyp2u1 decreased.…”

Section: Regulation Of Drug Metabolizing Enzymes During Inflammatimentioning

confidence: 99%

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

Mallick

Taneja

Moorthy

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

Introduction Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (SMDs), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/SMD treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

show abstract

“…Co-immunoprecipitation experiments were performed essentially as before [21] with antibodies specific for Smad2/3, NCoR, Flag, or isoform matched IgGs. After precipitation, the immunoprecipitants were analyzed by immunoblotting using antibodies against Flag, Smad2/ 3, or NCoR, respectively.…”

Section: Co-immunoprecipitationmentioning

confidence: 99%

TGF-β induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression

et al. 2015

Self Cite

View full text Add to dashboard Cite

The microRNA-30 family plays important roles in maintaining kidney homeostasis. Patients with focal segmental glomerulosclerosis (FSGS) have reduced miR-30 levels in glomerulus. TGF-β represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-β represses miR-30d in vitro. The human miR-30d promoter contains multiple copies of Smad binding element-like sequences. A fragment of 150 base pairs close to the transcription start site was negatively regulated by TGF-β to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-β specifically enhanced HDAC3 expression. Knockdown of HDAC3 by shRNA or a selective inhibitor RGFP966 significantly relieved the repression of miR-30d mRNA and the promoter transcription. TGF-β promoted HDAC3 association with Smad2/3 and NCoR and caused their accumulation at the putative Smad binding site on the miR-30d promoter, which was prohibited by TSA or RGFP966. Furthermore, TSA or RGFP966 treatment reversed TGF-β-induced up-regulation of miR-30d targets Notch1 and p53 and alleviated the podocyte cytoskeleton damage and apoptosis. Taken together, these findings pinpoint that TGF-β represses miR-30d through a Smad2/3-HDAC3-NCoR repression complex and provide novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies. Key message: MiR-30d promoter is negatively regulated by TGF-β. TGF-β down-regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-β. HDAC3 acts as a critical player in TGF-β-induced miR-30d repression and podocyte injuries.

show abstract

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Cited by 81 publications

References 44 publications

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Interplay between Nrf2 and NF-κB in Neuroinflammatory Diseases

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

TGF-β induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression

Contact Info

Product

Resources

About