LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions
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ABSTRACT:
PROVIDER: PRJNA664795 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12684550.fastq.gz | Fastqsanger.gz | |||
| SRR12684551.fastq.gz | Fastqsanger.gz | |||
| SRR12684552.fastq.gz | Fastqsanger.gz | |||
| SRR12684553.fastq.gz | Fastqsanger.gz | |||
| SRR12684554.fastq.gz | Fastqsanger.gz |
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Project description:Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to trigger such process was unknown to date. Using a genome wide CRISPR/Cas9 screen, we identified LRRC8A, which encodes a chloride channel subunit, as the gene most associated with cell survival under hypertonic conditions. Hypertonicity activates the p38 stress-activated protein kinase pathway and its downstream MSK1 kinase, which phosphorylates and activates LRRC8A. LRRC8A-mediated Cl efflux facilitates activation of the with-no-lysine (WNK) kinase pathway, which in turn, promotes electrolyte influx via Na+ /K+ /2Cl cotransporter (NKCC) and RVI under hypertonic stress. LRRC8A-S217A mutation impairs channel activation by MSK1, resulting in reduced RVI and cell survival. In summary, LRRC8A is key to bidirectional osmotic stress responses and cell survival under hypertonic conditions.
2021-05-29 | GSE158316 | GEO
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:Regulation of cell volume is essential for tissue homeostasis and cell viability. In response to hypertonic stress, cells need rapid electrolyte influx to compensate water loss and to prevent cell death in a process known as regulatory volume increase (RVI). However, the molecular component able to trigger such a process was unknown to date. Using a genome-wide CRISPR/Cas9 screen, we identified LRRC8A, which encodes a chloride channel subunit, as the gene most associated with cell survival under hypertonic conditions. Hypertonicity activates the p38 stress-activated protein kinase pathway and its downstream MSK1 kinase, which phosphorylates and activates LRRC8A. LRRC8A-mediated Cl- efflux facilitates activation of the with-no-lysine (WNK) kinase pathway, which in turn, promotes electrolyte influx via Na+/K+/2Cl- cotransporter (NKCC) and RVI under hypertonic stress. LRRC8A-S217A mutation impairs channel activation by MSK1, resulting in reduced RVI and cell survival. In summary, LRRC8A is key to bidirectional osmotic stress responses and cell survival under hypertonic conditions.
| S-EPMC8201826 | biostudies-literature
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: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: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:We reported the essential function of Lrrc8a on germline development
2020-05-01 | GSE112730 | GEO
Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).
2016-06-01 | E-GEOD-73589 | biostudies-arrayexpress
Project description:We examined the possible effects of hypertonic stress on Arabidopsis translatome using polysome profiling. We found that the translatome is partly and rapidly reprogrammed in response to hypertonic stress, and such translatome reprogramming is DCP5-dependent.
2022-01-20 | GSE193804 | GEO
Project description:Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function
| PRJNA1018950 | ENA