Actin polymerization by WASp limits nuclear envelope rupture and inflammation in macrophages I
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ABSTRACT:
PROVIDER: PRJNA1201748 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31802812_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802812_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802813_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802813_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802814_1.fastq.gz | Fastqsanger.gz |
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Project description:Actin polymerization by WASp limits nuclear envelope rupture and inflammation in macrophages
| PRJNA1201051 | ENA
Project description:Mutations in the immune-specific actin regulator WASp induce a proinflammatory state in myeloid cells, whose underlying causes remain poorly defined. Here, we applied microfabricated tools that mimic tissue mechanical forces to explore the role of WASp in connecting mechano-sensing to the activation of inflammatory responses in macrophages. We show that WASp-deficient macrophages carry nuclear structure alterations and undergo increased blebbing and nuclear rupture when exposed to mechanical confinement. High-resolution imaging indicates that WASp drives the formation of protective perinuclear actin structures in response to confinement. Functionally, WASp null macrophages respond to mechanical confinement by inducing a transcriptional profile consistent with the release of immunogenic DNA in the cytosol. The proinflammatory state of mechanically confined WASp-deficient macrophages depends, in part, on the cGAS-STING pathway of cytosolic DNA sensing. Together, these data uncover a WASp-dependent mechanism to restrict activation of inflammatory signalling in tissue macrophages and provide hints to target unabated inflammation in Wiskott-Aldrich Syndrome.
2025-03-26 | GSE285024 | GEO
Project description:Mutations in the immune-specific actin regulator WASp induce a proinflammatory state in myeloid cells, whose underlying causes remain poorly defined. Here, we applied microfabricated tools that mimic tissue mechanical forces to explore the role of WASp in connecting mechano-sensing to the activation of inflammatory responses in macrophages. We show that WASp-deficient macrophages carry nuclear structure alterations and undergo increased blebbing and nuclear rupture when exposed to mechanical confinement. High-resolution imaging indicates that WASp drives the formation of protective perinuclear actin structures in response to confinement. Functionally, WASp null macrophages respond to mechanical confinement by inducing a transcriptional profile consistent with the release of immunogenic DNA in the cytosol. The proinflammatory state of mechanically confined WASp-deficient macrophages depends, in part, on the cGAS-STING pathway of cytosolic DNA sensing. Together, these data uncover a WASp-dependent mechanism to restrict activation of inflammatory signalling in tissue macrophages and provide hints to target unabated inflammation in Wiskott-Aldrich Syndrome.
2024-12-25 | GSE285174 | GEO
Project description:Cell wall patterning is central to determining the shape and function of plant cells. Protoxylem and metaxylem vessel cells deposit banded and pitted cell walls, respectively, which enable their distinctive water transport capabilities, but the mechanisms that specify which cell wall pattern is laid down remain unknown. Here, we show that the pitted cell wall pattern in metaxylem vessels is specified by transcriptional control of actin polymerization. A newly isolated allele of KNOTTED-like homeobox transcription factor 7 (KNAT7) was associated with the formation of banded cell walls in metaxylem vessels. To identify the genes responsible for altering the cell wall pattern in knat7 xylem vessels, we performed an RNA-seq analysis of knat7. We used in vitro cultures of hypocotyls and cotyledons because the population of differentiating xylem cells in intact roots is tiny and these methods efficiently induce ectopic differentiation of xylem vessel elements. Formin Homology Domain-Containing Protein 11 (FH11) was upregulated in knat7 metaxylem, but expressed only in protoxylem vessels in wild-type plants. Loss of FH11 suppressed the knat7 phenotype. Conversely, ectopic overexpression of FH11 in metaxylems mimicked the knat7 phenotype. FH11 function required its plasma membrane anchoring and the actin polymerization activity. Actin polymerization by FH11 at the plasma membrane caused the dispersion of activated ROP GTPases, the determinant of pit formation. These results suggest that decontrol of actin polymerization at the plasma membrane abolishes the pitted cell wall formation and promotes the formation of banded cell walls in metaxylem vessels. This study unveils the importance of the proper control of actin polymerization on cell wall pattern specification.
2025-01-15 | GSE286145 | GEO
Project description:The protein product of the Early region 4 open reading frame 4 (E4orf4) of human adenovirus 2 is reported to exhibit a tumor-selective cell killing activity. Here, we show that E4orf4’s tumoricidal activity correlated with changes in perinuclear actomyosin contractility that are controlled by an interaction with the Par3 polarity protein. Surprisingly, E4orf4 enhanced apical-basal polarity in non-transformed mammary epithelial cells. In contrast, in tumorigenic cells, it induced a high incidence of actin-dependent nuclear bleb rupture. This process, which was regulated by the linker of nucleoskeleton and cytoskeleton (LINC) complex, promoted nuclear efflux of E4orf4 and the breakdown of the nuclear compartment. Significantly, Par3 also regulated the incidence of transient nuclear envelope rupture due to the reduced nuclear rigidity in cells depleted of lamins, in absence of E4orf4. Thus, using E4orf4 as a probing tool, we uncovered a so far un-appreciated role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.
2020-03-19 | PXD014329 | Pride
Project description:The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.
2023-10-09 | PXD040857 | Pride
Project description:The pleiotropic RTK Kit can provide cytoskeletal signals that define cell shape, positioning and migration, but the underlying mechanisms are less well understood. Here we provide evidence that Kit signals through WASP (Wiskott-Aldrich Syndrome Protein), the central hematopoietic actin nucleation- promoting factor and regulator of the cytoskeleton. KL-mediated gene expression in WT and WASP-deficient BMMCs was compared and revealed that approximately 30% of all Kit-induced changes were WASP-dependent. The results indicate that Kit signaling through WASP is necessary for normal Kit-mediated filopodia formation, cell survival and gene expression and provide new insight in the mechanism how WASP exerts a strong selective pressure in hematopoiesis.
2009-08-29 | E-MEXP-2282 | biostudies-arrayexpress
Project description:T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4 T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+ levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies, but does not interfere with immune synapse formation and cell proliferation. Ca2+-regulated actin polymerization in the nucleus allows CD4 T cells the rapid conversion of TCR signals into effector functions required for T cell help Identification of nuclear F-actin sensitive genes upon TCR signaling
2018-11-15 | GSE122531 | GEO
Project description:The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.
2023-10-09 | PXD043990 | Pride
Project description:Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an infant from progressive and severe pneumonia by Pseudomonas aeruginosa and poor wound healing. The younger sib was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. Apart from the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as transcriptional co-regulator. Degranulation was enhanced upon suboptimal neutrophil activation, while production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis and bacterial killing was found. Also monocyte-derived macrophages showed intact phagocytosis; lymphocyte counts and proliferative capacity were normal. Non-hematopoietic primary patient fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and filamentous actin (F-actin) content, most probably due to compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as most prominent features.
2020-03-16 | GSE134644 | GEO