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Results for “Formin”

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6 recordsLinked to original sources

PubMed2025

Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.

Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.

Formins↗

PubMed2024

SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.

The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.

RNA Polymerase II↗

PubMed2026

Rapidly progressive steroid-resistant focal segmental glomerulosclerosis associated with an INF2 exon 6 variant.

Variants in the inverted formin-2 (INF2) gene are a known cause of hereditary focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease. We report a case of rapidly progressive FSGS associated with a rare INF2 variant. A 12-year-old boy developed proteinuria and was diagnosed with FSGS at age 14 following a renal biopsy. Steroid therapy and subsequent immunosuppressive treatments, including plasma exchange, were ineffective. At age 15, a heterozygous missense variant in exon 6 of the INF2 gene (c.763G>A, p.Asp255Asn) was identified. Despite conservative management, the patient progressed to end-stage kidney disease at age 17. Although exon 6 variants are rarely reported, the present case showed a relatively aggressive renal course.

Humans↗

PubMed2024

Cytoskeletal mechanisms regulating attaching/effacing bacteria interactions with host cells: It takes a village to build the pedestal.

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), developed a unique mechanism to remodel the actin cytoskeleton that involves the assembly of actin filament-rich pedestals beneath the bacterial attachment sites. Actin pedestal assembly is driven by bacterial effectors injected into the host cells, and this structure is important for EPEC and EHEC colonization. While the interplay between bacterial effectors and the actin polymerization machinery of host cells is well-understood, how other mechanisms of actin filament remodelling regulate pedestal assembly and bacterial attachment are poorly investigated. This review discusses the gaps in our understanding of the complexity of the actin cytoskeletal remodelling during EPEC and EHEC infection. We describe possible roles of actin depolymerizing, crosslinking and motor proteins in pedestal dynamics, and bacterial interactions with the host cells. We also discuss the biological significance of pedestal assembly for bacterial infection.

Humans↗

PubMed2026

TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.

Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predominant renal manifestations are uncommon and may complicate diagnosis. We report a child presenting with developmental delay, failure to thrive, lactic acidosis, and distal renal tubular acidosis (dRTA), raising suspicion of an underlying mitochondrial disorder. Whole exome sequencing (WES) analysis identified a homozygous intron-exon boundary deletion of 31 bp (c.463-19_474del) in TTC19 predicted to disrupt splicing, with functional evidence demonstrating aberrant transcript formation, reduced gene expression, and mitochondrial dysfunction in patient-derived fibroblasts. Based on the biochemical findings, re-analysis of exome data revealed a novel homozygous canonical splice-site variant (c.783-1G>A) in FMNL2. The splicing assay showed the skipping of exon 9, and reduced expression in the fibroblasts. This case expands the clinical spectrum of TTC19-related mitochondrial complex III deficiency with early-onset renal tubular acidosis. While TTC19 is the most plausible primary disease-causing gene, the functional disruption of FMNL2 suggests a potential contributory role or association with the renal phenotype. Hence, these findings highlight the importance of genomic re-analysis along with functional studies in resolving complex multisystem disorders.

Female↗

PubMed2003

A role for VASP in RhoA-Diaphanous signalling to actin dynamics and SRF activity.

Vasodilator-stimulated phosphoprotein (VASP) is involved in multiple actin-mediated processes, including regulation of serum response factor (SRF) activity. We used the SRF transcriptional assay to define functional domains in VASP and to show that they coincide with those required for F-actin accumulation, as determined by a quantitative FACS assay. We identified inactive VASP mutants that can interfere both with F-actin assembly and with SRF activation by wild-type VASP. These VASP mutants also inhibit actin-based motility of Vaccinia virus and Shigella flexneri. VASP-induced F-actin accumulation and SRF activation require both functional Rho and its effector mDia, and conversely, mDia-mediated SRF activation is critically dependent on functional VASP. VASP and mDia also associate physically in vivo. These findings show that VASP and mDia function cooperatively downstream of Rho to control F-actin assembly and SRF activity.

3T3 Cells↗