Vimentin Cytoskeleton Collapses in Response to the Small Molecule Inhibitor of FH2 domains (SMIFH2)-induced Electrophilic Stress.

The type III intermediate filament protein vimentin plays an integral role in cell homeostasis and disease progression during fibrosis and cancer invasion. Previous work demonstrated that the pan-formin inhibitor SMIFH2 induced a perinuclear collapse of the vimentin network, suggesting formins may regulate vimentin cytoskeleton organization. However, despite the designed function of SMIFH2 to inhibit formin FH2 domain-actin interactions, several major off-target effects of SMIFH2 have been reported, including inhibition of myosin family ATPase activity. SMIFH2 is also highly electrophilic, potentially reacting with nucleophilic residues within proteins other than formins. Therefore, we sought to determine the mechanism by which SMIFH2 disrupts the vimentin cytoskeleton. Depletion of specific formin proteins, targeted actin cytoskeleton disruption, or myosin family ATPase inhibition failed to replicate the SMIFH2 effect on the vimentin network. However, treatment with other electrophilic reagents including prostaglandin A, reproduced the SMIFH2-mediated vimentin collapse, F-actin cytoskeletal changes, and activation of the Nrf2 stress sensory pathway. Additionally, FRAP analysis revealed that SMIFH2 inhibits vimentin filament dynamics, which was rescued by mutating the nucleophilic vimentin C328 residue. Thus, SMIFH2 disrupts the vimentin network due to its reactivity as an electrophilic species. This study reinforces the role of vimentin as a key stress sensor. [Media: see text] [Media: see text] [Media: see text] [Media: see text].

• Publication year

  2025

• Venue

  Molecular Biology of the Cell

• Publication date

  2025-10-15

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1091/mbc.E25-05-0228PMID 41091574PMCID PMC12636697
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Reconstitution of cytolinker-mediated crosstalk between actin and vimentin

  2024cited by this paper
• Interplay of oxidative stress, cellular communication and signaling pathways in cancer

  2024cited by this paper
• Decisive role of mDia-family formins in cell cortex function of highly adherent cells

  2024cited by this paper
• Vimentin single cysteine residue acts as a tunable sensor for network organization and as a key for actin remodeling in response to oxidants and electrophiles

  2023cited by this paper
• RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress

  2023cited by this paper
• Plectin linkages are mechanosensitive and required for the nuclear piston mechanism of three-dimensional cell migration

  2022cited by this paper
• Oxidation and reduction of actin: Origin, impact in vitro and functional consequences in vivo.

  2022cited by this paper
• Alterations to the broad-spectrum formin inhibitor SMIFH2 modulate potency but not specificity

  2022cited by this paper
• Force-dependent activation of actin elongation factor mDia1 protects the cytoskeleton from mechanical damage and promotes stress fiber repair.

  2021cited by this paper
• Formin Activity and mDia1 Contribute to Maintain Axon Initial Segment Composition and Structure

  2021cited by this paper
• Vimentin intermediate filaments and filamentous actin form unexpected interpenetrating networks that redefine the cell cortex

  2021cited by this paper
• Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

  2021cited by this paper
• β-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes

  2021cited by this paper
• Vimentin protects differentiating stem cells from stress

  2020cited by this paper
• Vimentin intermediate filaments stabilize dynamic microtubules by direct interactions

  2020cited by this paper
• The formin inhibitor SMIFH2 inhibits members of the myosin superfamily

  2020cited by this paper
• Type III intermediate filaments as targets and effectors of electrophiles and oxidants

  2020cited by this paper
• The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts

  2019cited by this paper
• Vimentin disruption by lipoxidation and electrophiles: Role of the cysteine residue and filament dynamics

  2019cited by this paper
• The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment

  2019cited by this paper
• High stretchability, strength, and toughness of living cells enabled by hyperelastic vimentin intermediate filaments

  2019cited by this paper
• INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division

  2018cited by this paper
• Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice

  2018cited by this paper
• Vimentin fibers orient traction stress

  2017cited by this paper
• Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA

  2017cited by this paper
• Redox regulation of the actin cytoskeleton and its role in the vascular system

  2017cited by this paper
• Vimentin Intermediate Filaments Template Microtubule Networks to Enhance Persistence in Cell Polarity and Directed Migration.

  2016cited by this paper
• An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells

  2016cited by this paper
• Hic-5 Remodeling of the Stromal Matrix Promotes Breast Tumor Progression

  2016cited by this paper
• SMIFH2 has effects on Formins and p53 that perturb the cell cytoskeleton

  2015cited by this paper
• Bidirectional Interplay between Vimentin Intermediate Filaments and Contractile Actin Stress Fibers.

  2015cited by this paper
• Microtubule-dependent transport and dynamics of vimentin intermediate filaments

  2015cited by this paper
• Vimentin filament organization and stress sensing depend on its single cysteine residue and zinc binding

  2015cited by this paper
• Formins as effector proteins of Rho GTPases

  2014cited by this paper
• Microtubule‐dependent transport of vimentin filament precursors is regulated by actin and by the concerted action of Rho‐ and p21‐activated kinases

  2014cited by this paper
• Formins at a glance

  2013cited by this paper
• The multiplicity of human formins: Expression patterns in cells and tissues

  2013cited by this paper
• The Focal Adhesion Analysis Server: a web tool for analyzing focal adhesion dynamics

  2013cited by this paper
• Role of vimentin in cell migration

  2013cited by this paper
• Vimentin intermediate filaments modulate the motility of mitochondria

  2011cited by this paper
• Vimentin in cancer and its potential as a molecular target for cancer therapy

  2011cited by this paper
• Observations on screening-based research and some concerning trends in the literature.

  2010cited by this paper
• Unleashing formins to remodel the actin and microtubule cytoskeletons

  2010cited by this paper
• Fifteen formins for an actin filament: a molecular view on the regulation of human formins.

  2010cited by this paper
• Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition

  2010cited by this paper
• Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly.

  2009cited by this paper
• Vimentin supports mitochondrial morphology and organization.

  2008cited by this paper
• Novel functions of vimentin in cell adhesion, migration, and signaling.

  2007cited by this paper
• Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1

  2006cited by this paper
• A novel mechanism for the formation of actin-filament bundles by a nonprocessive formin.

  2006cited by this paper
• A Direct Interaction between Actin and Vimentin Filaments Mediated by the Tail Domain of Vimentin*

  2006cited by this paper
• Identification of novel protein targets for modification by 15-deoxy-Delta12,14-prostaglandin J2 in mesangial cells reveals multiple interactions with the cytoskeleton.

  2005cited by this paper
• Formin proteins: a domain-based approach.

  2005cited by this paper
• mDia-interacting Protein Acts Downstream of Rho-mDia and Modifies Src Activation and Stress Fiber Formation*

  2001cited by this paper
• Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.

  1999cited by this paper
• An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.

  1997cited by this paper
• Characterization of disulfide crosslink formation of human vimentin at the dimer, tetramer, and intermediate filament levels.

  1996cited by this paper
• Intermediate filament collapse is an ATP-dependent and actin-dependent process.

  1989cited by this paper

• No citing papers are available for this paper.