The volume-regulated anion channel LRRC8 is involved in initiation of epidermal differentiation and is deregulated in psoriasis
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ABSTRACT:
PROVIDER: PRJNA1221294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32280358_1.fastq.gz | Fastqsanger.gz | |||
| SRR32280358_2.fastq.gz | Fastqsanger.gz | |||
| SRR32280359_1.fastq.gz | Fastqsanger.gz | |||
| SRR32280359_2.fastq.gz | Fastqsanger.gz | |||
| SRR32280360_1.fastq.gz | Fastqsanger.gz |
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Project description:Recent studies have shown that LRRC8A, the essential subunit of the volume-regulated anion channel LRRC8, which is responsible for mediating cell volume regulation during hypotonic stress, is predominantly localized in the basal layer of the epidermis. This prompted us to investigate whether LRRC8A plays a role in maintaining epidermal homeostasis by regulating key processes initiated in this layer, such as cell proliferation and/or differentiation. LRRC8A was found to be strongly upregulated in transiently amplifying cells at the onset of differentiation. While LRRC8A mRNA remains high when keratinocytes mature further, the LRRC8A protein is drastically downregulated. Interference with LRRC8A expression at this step inhibits transition of keratinocyte stem cells into transiently amplifying cells and impairs terminal differentiation. As psoriasis is a common chronic inflammatory skin disease characterized by disturbed epidermal differentiation and aberrant function of transiently amplifying cells, we investigated the involvement of LRRC8A in this disease. Indeed, LRRC8A was strongly decreased in lesional psoriatic skin, which could also be mimicked in vitro using Th1/Th17 cytokine mixes. Thus, our data suggest that LRRC8 could serve as a therapeutic target for the topical treatment strategies of psoriatic lesions by restoring the capacity of keratinocytes to initiate differentiation.
2025-02-09 | GSE289090 | GEO
Project description:To become fully functional effector T cells, naïve T cells undergo a drastic metabolic status shift from quiescence to substantial biosynthesis. The synthesis of biomass initiated by T cell receptor (TCR) signals drives the cell volume increase during T cell activation (T lymphoblast), which resembles the slowest extreme of hypotonic cell swelling. However, the fundamental role of cell volume regulation in TCR signaling during T lymphoblast and its underlying mechanisms remain a long-standing enigma. Here we show that optimal T cell activation and function require appropriate cell volume regulation by regulated volume decrease (RVD) mediated via volume-regulated anion channels (VRACs) during T cell blast. Pharmacological blockade of VRACs and genetic deletion of LRRC8A in T cells, the essential component of VRACs, impair T cell activation and function, particularly under weak TCR stimulation, such as low-affinity TCR-pMHC engagement and unsaturated anti-CD3e crosslinking. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles driven by various TCR signal strengths, revealing the prominent effects of cell volume regulation for T cell functions. More importantly, LRRC8A-deficient mice have defective antiviral immunity and obstacles in effector-memory transition of CD8+ T cells. Furthermore, LRRC8A escorts the thymic selection of T cells and shapes the T cell repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via RVD during T cell blast induced by activation-driven intracellular osmolytes accumulation to keep the proximal TCR signaling molecules at adequate density. T cell blast driven by TCR signal feedbacks to control T cell activation. Together, our results reveal a previously unappreciated layer of T cell activation regulation that LRRC8A acts as a cell volume controlling "valve" to facilitate T cell activation and function
2023-09-23 | GSE243574 | GEO
Project description:Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function
| PRJNA1018950 | ENA
Project description:The volume-regulated anion channel (VRAC) is a hexameric complex formed by LRRC8 proteins. VRACs are responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling by mediating the efflux of chloride. Besides chloride, LRRC8 proteins transport other molecules including immunomodulatory cyclic dinucleotides (CDNs) such as 2’3’cGAMP. Here we identify LRRC8C as a critical component of VRACs in T cells, where its deletion abolishes VRAC currents and RVD. We find that LRRC8C mediates the transport of 2’3’cGAMP in T cells. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production in vitro and enhanced T cell mediated immunity in vivo. We used RNA sequencing of CD4+ T cells from wild-type (WT) and Lrrc8c-/- mice to determine the effects of impaired cGAMP signaling in T cells. T cells of Lrrc8c-/- mice had impaired p53 signaling which was associated with decreased p53 expression. We found that uptake of 2’3’cGAMP and other CDNs via LRRC8C results in STING activation and p53 accumulation. Inhibition of STING in WT T cells recapitulates the phenotype of LRRC8C-deficient T cells whereas overexpression of p53 inhibits enhanced T cell function in the absence of LRRC8C. These findings establish cGAMP uptake through LRRC8C and subsequent STING-p53 signaling as a novel inhibitory signaling pathway in T cells and adaptive immunity.
2021-12-31 | GSE163679 | GEO
Project description:Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC), which is activated by cell swelling and transports halide anions and small organic compounds. Despite the recent availability of the cryo-EM structures of homo-hexameric LRRC8A, the structural basis of how LRRC8 isoforms other than LRRC8A contribute to the functional diversity of VRAC has remained elusive. In this study, we confirmed the absence of LRRC8 isoforms in the purified HsLRRC8D using mass spectrometry, and the structure of the HsLRRC8D homomer was analyzed using the cryo-EM. This work provides structural insights into the functional diversity of the LRRC8 protein family.
2020-05-27 | PXD018780 | Pride
Project description:Deficient LRRC8A-dependent Volume-Regulated Anion Channel (VRAC) activity is associated with male infertility in mouse and humans
| PRJNA448855 | ENA
Project description:The volume regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling
| PRJNA687046 | ENA
Project description:Volume-regulated anion channels participate in the cellular response to osmotic swelling. These membrane proteins are heteromers of LRRC8 family members whose composition determines permeation properties. Although structures of the obligatory LRRC8A subunit have previously defined the architecture of VRACs, the organization of heteromeric channels has remained elusive. Here we have closed this gap by the structural characterization of channels consisting of LRRC8A and C. Like homomeric LRRC8A, these proteins assemble as hexamers. Despite the twelve possible arrangements, we find a single predominant species with an A/C ratio of two. In this assembly, the four LRRCA subunits cluster in their preferred conformation observed in homomers as pairs of closely interacting proteins that stabilize a closed state of the channel. In contrast, the two interacting LRRC8C-subunits show a larger flexibility, underlining their role in the destabilization of the tightly packed A subunits, thereby enhancing the activation properties of the protein.
2023-01-03 | PXD035350 | Pride
Project description:Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here we show that the expression of Ovol1 transcription factor is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod (IMQ). Using bulk and single-cell RNA-sequencing, we identify molecular changes in the epidermal, fibroblast and immune cells of Ovol1-deficient skin that reflect altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1 signaling in the microenvironment of IMQ-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for Ovol1 in curtailing psoriasis-like inflammation and the associated skin pathology
2021-12-01 | GSE159704 | GEO
Project description:Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective. Several ion channels that regulate membrane potential, cytosolic Ca2+ concentration and cell volume in GBM cells play significant roles in sustaining these processes. Among them, the volume-regulated anion channel (VRAC), which mediates the swelling-activated chloride current (IClswell) and is highly expressed in GBM cells, arguably plays a major role. VRAC is primarily involved in reestablishing the original cell volume that may be lost under several physiopathological conditions, but also in sustaining the shape and cell volume changes needed for cell migration and proliferation. While experimentally VRAC is activated by exposing cells to hypotonic solutions that cause the increase of cell volume, in vivo it is thought to be controlled by several different stimuli and modulators. In this review we focus on our recent work showing that two conditions normally occurring in pathological GBM tissues, namely high serum levels and severe hypoxia, were both able to activate VRAC, and their activation was found to promote cell migration and resistance to cell death, both features enhancing GBM malignancy. Also, the fact that the signal transduction pathway leading to VRAC activation appears to involve GBM specific intracellular components, such as diacylglicerol kinase and phosphatidic acid, reportedly not involved in the activation of VRAC in healthy tissues, is a relevant finding. Based on these observations and the impact of VRAC in the physiopathology of GBM, targeting this channel or its intracellular regulators may represent an effective strategy to contrast this lethal tumor.
| S-EPMC6468384 | biostudies-literature