Perinuclear force regulates SUN2 dynamics and distribution on the nuclear envelope for proper nuclear mechanotransduction
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ABSTRACT:
PROVIDER: PRJNA887402 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21815088_1.fastq.gz | Fastqsanger.gz | |||
| SRR21815088_2.fastq.gz | Fastqsanger.gz | |||
| SRR21815089_1.fastq.gz | Fastqsanger.gz | |||
| SRR21815089_2.fastq.gz | Fastqsanger.gz | |||
| SRR21815090_1.fastq.gz | Fastqsanger.gz |
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Project description:SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1 and Syne homology) proteins are constituents of the inner and outer nuclear membranes. They interact in the perinuclear space via carboxy-terminal SUN-KASH domains to form the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex thereby bridging the nuclear envelope. LINC complexes sustain numerous biological processes by connecting chromatin with the cytoplasmic force generating machinery. Here we show that the coiled-coil domains of SUN-1 are required for oligomerization and retention of the protein in the nuclear envelope, especially at later stages of female gametogenesis. Consistently, deletion of the coiled coil domain makes SUN-1 sensitive to unilateral force generation across the nuclear membrane. However, absence of this domain does not lead to different expression levels of sun-1 and other known meiotic genes in the mutant compared to wild type. Premature loss of SUN-1 from the nuclear envelope leads to embryonic death due to loss of centrosome-nuclear envelope attachment. However, in contrast to previous notions we can show that the coiled-coil domain is dispensable for functional LINC complex formation, exemplified by successful chromosome sorting and synapsis in meiotic prophase I in their absence.
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Project description:The transposon silencing piRNAs are produced from precursors that are encoded by heterochromatic clusters and processed in the perinuclear nuage. We show that the Drosophila nuclear DEAD box protein UAP56, previously implicated in mRNA splicing and nuclear export, co-localizes with the cluster-associated HP1 homologue Rhino. Prominent nuclear foci containing Rhi and UAP56 localize directly across the nuclear envelope from Vasa, a conserved DEAD box protein and core nuage component that is required for piRNA production, and piRNA precursors immunoprecipitate with both UAP56 and Vasa. A uap56 point mutation that prevents UAP56 protein co-localization with Rhino also disrupts nuage organization, transposon silencing, and expression of dual strand piRNA clusters. By contrast, this allele significantly increases ectopic piRNAs from protein coding genes. We therefore propose that UAP56 and Vasa organize a piRNA-processing compartment that spans the nuclear envelope, increasing the efficiency and specificity of piRNA biogenesis. 3 replicates of each sample (uap56, vasa), total RNA samples hybridized to tiling array.
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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.
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Project description:The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.
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