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Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE107266 | GEO | 2017/11/23

SECONDARY ACCESSION(S): PRJNA419494

REPOSITORIES: GEO

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Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Epidermis ssRNA-Seq]

Project description:Arp2/3 complex assembles branched actin filaments key to many cellular processes, but its organismal roles remain poorly understood. Here we employed conditional arpc4 knockout mice to study the function of the Arp2/3 complex in the epidermis.We found that depletion of the Arp2/3 complex by knockout of arpc4 results in skin abnormalities at birth that evolve into a severe psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2. Knockout of arpc4 in cultured keratinocytes was sufficient to induce nuclear accumulation of Nrf2, upregulation of Nrf2-target genes and decreased filamentous actin levels. Furthermore, pharmacological inhibition of the Arp2/3 complex unmasked the role of branched actin filaments in Nrf2 regulation. Consistently, we unveiled that Nrf2 associates with the actin cytoskeleton in cells and binds to filamentous actin in vitro Finally, we discovered that Arpc4 is downregulated in both human and mouse psoriatic epidermis. Thus, the Arp2/3 complex affects keratinocytes' shape and transcriptome through an actin-based cell-autonomous mechanism that influences epidermal morphogenesis and homeostasis.

2017-11-23 | GSE107265 | GEO

Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Keratinocytes ssRNA-Seq]

2017-11-23 | GSE107264 | GEO

Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2

Project description:Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2

| PRJNA419494 | ENA

Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Epidermis ssRNA-Seq]

Project description:Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Epidermis ssRNA-Seq]

| PRJNA419518 | ENA

Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Keratinocytes ssRNA-Seq]

Project description:Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Keratinocytes ssRNA-Seq]

| PRJNA419517 | ENA

Genetic hyperactivation of Nrf2 causes larval lethality in Keap1a and Keap1b-double-knockout zebrafish.

Project description:The Keap1-Nrf2 pathway is an evolutionarily conserved mechanism that protects cells from oxidative stress and electrophiles. Keap1 is a repressor of Nrf2 in normal cellular conditions but also a stress sensor for Nrf2 activation. Interestingly, fish and amphibians have two Keap1s (Keap1a and Keap1b), of which Keap1b is the ortholog of mammalian Keap1. Keap1a, on the other hand, is a gene found only in fish and amphibians, having been lost during the evolution to amniotes. We have previously shown that keap1b-knockout zebrafish have increased Nrf2 activity and reduced response to certain Nrf2-activating compounds but that they grow normally to adulthood. This may be because the remaining keap1a suppresses the hyperactivation of Nrf2, which is responsible for the post-natal lethality of Keap1-knockout mice. In this study, we analyzed keap1a;keap1b-double-knockout zebrafish to test this hypothesis. We found that keap1a;keap1b-double-knockout zebrafish, like Keap1-knockout mice, showed eating defects and were lethal within a week of hatching. Genetic introduction of the Nrf2 mutation rescued both the eating defects and the larval lethality, indicating that Nrf2 hyperactivation is the cause. However, unlike Keap1-knockout mice, keap1a;keap1b-double-knockout zebrafish showed no physical blockage of the food pathway; moreover, the cause of death was not directly related to eating defects. RNA-sequencing analysis revealed that keap1a;keap1b-double-knockout larvae showed extraordinarily high expression of known Nrf2-target genes as well as decreased expression of visual cycle genes. Finally, trigonelline or brusatol partially rescued the lethality of keap1a;keap1b-double-knockout larvae, suggesting that they can serve as an in vivo evaluation system for Nrf2-inhibiting compounds.

| S-EPMC10031532 | biostudies-literature

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease.

Project description:Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott-Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

| S-EPMC5382316 | biostudies-literature

Modelling epidermis homoeostasis and psoriasis pathogenesis.

Project description:We present a computational model to study the spatio-temporal dynamics of epidermis homoeostasis under normal and pathological conditions. The model consists of a population kinetics model of the central transition pathway of keratinocyte proliferation, differentiation and loss and an agent-based model that propagates cell movements and generates the stratified epidermis. The model recapitulates observed homoeostatic cell density distribution, the epidermal turnover time and the multilayered tissue structure. We extend the model to study the onset, recurrence and phototherapy-induced remission of psoriasis. The model considers psoriasis as a parallel homoeostasis of normal and psoriatic keratinocytes originated from a shared stem cell (SC) niche environment and predicts two homoeostatic modes of psoriasis: a disease mode and a quiescent mode. Interconversion between the two modes can be controlled by interactions between psoriatic SCs and the immune system and by normal and psoriatic SCs competing for growth niches. The prediction of a quiescent state potentially explains the efficacy of multi-episode UVB irradiation therapy and recurrence of psoriasis plaques, which can further guide designs of therapeutics that specifically target the immune system and/or the keratinocytes.

| S-EPMC4305409 | biostudies-literature

Epidermis-Intrinsic Transcription Factor Ovol1 Coordinately Regulates Barrier Maintenance and Neutrophil Accumulation in Psoriasis-Like Inflammation.

Project description:Skin epidermis constitutes the exterior barrier that protects the body from dehydration and environmental assaults. Barrier defects underlie common inflammatory skin diseases, but the molecular mechanisms that maintain barrier integrity and regulate epidermal-immune cell cross-talk in inflamed skin are not fully understood. In this study, we show that skin epithelia-specific deletion of Ovol1, which encodes a skin disease‒linked transcriptional repressor, impairs the epidermal barrier and aggravates psoriasis-like skin inflammation in mice in part by enhancing neutrophil accumulation and abscess formation. Through molecular studies, we identify IL-33, a cytokine with known pro-inflammatory and anti-inflammatory activities, and Cxcl1, a neutrophil-attracting chemokine, as potential weak and strong direct targets of Ovol1, respectively. Furthermore, we provide functional evidence that elevated Il33 expression reduces disease severity in imiquimod-treated Ovol1-deficient mice, whereas persistent accumulation and epidermal migration of neutrophils exacerbate it. Collectively, our study uncovers the importance of an epidermally expressed transcription factor that regulates both the integrity of the epidermal barrier and the behavior of neutrophils in psoriasis-like inflammation.

| S-EPMC9968377 | biostudies-literature

TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.

Project description:Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

| S-EPMC10776564 | biostudies-literature

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