Cingulin and paracingulin tether myosins-2 to junctions to mechanoregulate the plasma membrane

The Journal of Cell Biology, Год журнала: 2023, Номер 222(7)

Опубликована: Май 19, 2023

The mechanisms that regulate the spatial sorting of nonmuscle myosins-2 (NM2) isoforms and couple them mechanically to plasma membrane are unclear. Here we show cytoplasmic junctional proteins cingulin (CGN) paracingulin (CGNL1) interact directly with NM2s through their C-terminal coiled-coil sequences. CGN binds strongly NM2B, CGNL1 NM2A NM2B. Knockout (KO), exogenous expression, rescue experiments WT mutant NM2-binding region is required for accumulation ZO-1, ZO-3, phalloidin-labeled actin filaments, maintenance tight junction tortuosity apical stiffness. expression promotes both NM2B its KO results in myosin-dependent fragmentation adherens complexes. These reveal a mechanism localization indicate that, by binding NM2s, actomyosin cytoskeleton protein complexes mechanoregulate membrane.

Язык: Английский

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The role of Rho GTPase family in cochlear hair cells and hearing

Neural Regeneration Research, Год журнала: 2023, Номер 18(10), С. 2167 - 2167

Опубликована: Янв. 1, 2023

Rho GTPases are essential regulators of the actin cytoskeleton. They involved in various physiological and biochemical processes such as regulation cytoskeleton dynamics, development, proliferation, survival, regeneration. During development cochlear hair cells, activated by extracellular signals through membrane receptors to further stimulate multiple downstream effectors. Specifically, RhoA, Cdc42, Rac1, members classical subfamily GTPase family, regulate maintenance cilia inducing polymerization monomers stabilizing filaments. In addition, they also normal morphology orientation ciliary bundles auditory which is an important element cell polarity regulation. Moreover, actin-related pathways mediated Rac1 play a role motility outer indicating that function crucial highly polar sensory system. this review, we focus on expression cells how these small molecules participate bundle morphogenesis movement. We discuss progress current research investigating use drug targets for deafness treatment.

Язык: Английский

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Zyxin contributes to coupling between cell junctions and contractile actomyosin networks during apical constriction

PLoS Genetics, Год журнала: 2023, Номер 19(3), С. e1010319 - e1010319

Опубликована: Март 28, 2023

One of the most common cell shape changes driving morphogenesis in diverse animals is constriction apical surface. Apical depends on contraction an actomyosin network cortex, but such networks have been shown to undergo continual, conveyor belt-like contractions before shrinking surface begins. This finding suggests that not necessarily triggered by networks, rather can be unidentified, temporally-regulated mechanical links between and junctions. Here, we used C . elegans gastrulation as a model seek genes contribute dynamic linkage. We found α-catenin β-catenin initially failed move centripetally with contracting cortical suggesting linkage regulated intact cadherin-catenin complexes actomyosin. proteomic transcriptomic approaches identify new players, including candidate linkers AFD-1/afadin ZYX-1/zyxin, contributing gastrulation. ZYX-1/zyxin among family LIM domain proteins transcripts become enriched multiple cells just they constriction. developed semi-automated image analysis tool it find contributes cell-cell junctions’ centripetal movement concert networks. These results several gastrulation, zyxin key protein important for effectively pull junctions inward during The transcriptional upregulation specific points one way developmental patterning spatiotemporally regulates biological mechanisms vivo Because related membrane-cytoskeleton other systems, anticipate its roles regulating this manner may conserved.

Язык: Английский

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Mechanical control of neural plate folding by apical domain alteration

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 20, 2023

Abstract Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding not well understood. At onset Xenopus folding, we observed alternation apically constricted expanded cells. This apical domain heterogeneity was accompanied by biased orientation along anteroposterior axis, especially at plate hinges, required planar polarity signaling. Vertex models suggested that dispersed isotropically constricting cells can cause elongation adjacent Consistently, ectoderm, cell-autonomous constriction neighbor expansion. Thus, a subset may initiate bending, whereas ‘tug-of-war’ contest between force-generating responding reduces its shrinking body axis. mechanism an alternative anisotropic junctions are perpendicular We propose reflect polarity-dependent mechanical forces operating during folding.

Язык: Английский

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LIM domain only 7: a novel driver of immune evasion through regulatory T cell differentiation and chemotaxis in pancreatic ductal adenocarcinoma

Cell Death and Differentiation, Год журнала: 2024, Номер unknown

Опубликована: Авг. 14, 2024

Abstract With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically “cold” tumor, exhibits limited responsiveness to immunotherapy. This study aimed address the urgent need uncover PDAC’s immune microenvironment heterogeneity identify molecular mechanisms driving evasion. Using single-cell RNA sequencing datasets spatial proteomics, we discovered LIM domain only 7 (LMO7) PDAC cells previously unrecognized driver of evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T (Tregs) dysfunctional CD8 + cells. A series vitro vivo experiments demonstrated LMO7’s significant role promoting differentiation chemotaxis while inhibiting natural killer cytotoxicity. Mechanistically, LMO7, its domain, directly bound promoted ubiquitination degradation Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-β) C-C motif chemokine ligand 5 (CCL5) expression by binding sites 2 I/III, respectively. Elevated TGF-β CCL5 levels contribute enrichment, inducing PDAC. Combined treatment TGF-β/CCL5 antibodies, along inhibition, effectively reversed PDAC, activated response, prolonged mouse survival. Therefore, this identified novel facilitator enrichment cytotoxic effector functions. Targeting LMO7-Foxp1-TGF-β/CCL5 axis holds promise therapeutic

Язык: Английский

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Architecture of the cortical actomyosin network driving apical constriction in C. elegans

The Journal of Cell Biology, Год журнала: 2023, Номер 222(9)

Опубликована: Июнь 23, 2023

Apical constriction is a cell shape change that drives key morphogenetic events during development, including gastrulation and neural tube formation. The forces driving apical are primarily generated through the contraction of apicolateral and/or medioapical actomyosin networks. In Drosophila ventral furrow, network has sarcomere-like architecture, with radially polarized actin filaments centrally enriched non-muscle myosin II activating kinase. To determine if this broadly conserved architecture constriction, we examined C. elegans gastrulation, in which two endodermal precursor cells internalize from surface embryo. Quantification protein localization showed neither NMY-2 nor myosin-activating kinase MRCK-1 at center apex. Further, visualization barbed- pointed-end capping proteins revealed do not exhibit radial polarization Our results demonstrate apically constrict using mixed-polarity filament activator distributed throughout network. Taken together observations made other organisms, our diverse architectures used animal to accomplish constriction.

Язык: Английский

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Actin-dependent recruitment of AGO2 to the zonula adherens

Molecular Biology of the Cell, Год журнала: 2023, Номер 34(13)

Опубликована: Окт. 11, 2023

Adherens junctions are cadherin-based structures critical for cellular architecture. E-cadherin in mature epithelial cell monolayers tether to an apical actomyosin ring form the zonula adherens (ZA). We have previously shown that junction protein PLEKHA7 associates with and regulates function of core RNA interference (RNAi) component AGO2 specifically at ZA. However, mechanism mediating recruitment ZA remained unexplored. Here, we reveal this ZA-specific depends on both structural tensile integrity cytoskeleton. found depletion not only PLEKHA7, but also either three PLEKHA7-interacting, LIM-domain family proteins, namely LMO7, LIMCH1, PDLIM1, results disruption organization tension, as well junctional localization its miRNA-binding ability. show binds Myosin IIB PDLIM1 all disrupt interaction These demonstrate is sensitive perturbations, introducing concept mechanosensitive RNAi machinery, potential implications tissue remodeling disease.

Язык: Английский

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A multi-tiered mechanical mechanism shapes the early neural plate

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июнь 21, 2023

Abstract The formation of complex tissues during embryonic development requires an intricate spatiotemporal coordination local mechanical processes regulating global tissue morphogenesis. Here, we uncover a novel mechanism that mechanically regulates the shape anterior neural plate (ANP), vital forebrain precursor, zebrafish gastrulation. Combining in vivo and silico approaches reveal ANP is shaped by flows regulated distinct force generating processes. We show mesendoderm migration E-cadherin-dependent differential interactions control flow regimes neuroectoderm. Initial opposing lead to progressive folding neuroectoderm internalisation which turn provide forces driving reshaping. find convergent extension dispensable for but required extension. Our results highlight how regulation coupling different between embryo controls first event developing brain.

Язык: Английский

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Zyxin contributes to coupling between cell junctions and contractile actomyosin networks during apical constriction

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Июль 4, 2022

Abstract One of the most common cell shape changes driving morphogenesis in diverse animals is constriction apical surface. Apical depends on contraction an actomyosin network cortex, but such networks have been shown to undergo continual, conveyor belt-like contractions before shrinking surface begins. This finding suggests that not necessarily triggered by networks, rather can be unidentified, temporally-regulated mechanical links between and junctions. Here, we used C. elegans gastrulation as a model seek genes contribute dynamic linkage. We found α-catenin β-catenin initially failed move centripetally with contracting cortical suggesting linkage regulated intact cadherin-catenin complexes actomyosin. proteomic transcriptomic approaches identify new players, including candidate linkers AFD-1/afadin ZYX-1/zyxin, contributing gastrulation. ZYX-1/zyxin among family LIM domain proteins transcripts become enriched multiple cells just they constriction. developed semi-automated image analysis tool describe rates myosin membrane movement, which then discover contributes cell-cell junctions’ centripetal movement concert networks. These results several gastrulation, zyxin key protein important for effectively pull junctions inward during The transcriptional upregulation specific points one way developmental patterning spatiotemporally regulates biological mechanisms vivo . Because related membrane-cytoskeleton other systems, anticipate its roles regulating this manner may conserved.

Язык: Английский

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Coordination of LMO7 with FAK Signaling Sustains Epithelial Integrity in Renal Epithelia Exposed to Osmotic Pressure

Cells, Год журнала: 2022, Номер 11(23), С. 3805 - 3805

Опубликована: Ноя. 28, 2022

The kidney epithelial barrier has multifaceted functions in body fluids, electrolyte homeostasis, and urine production. renal (REB) frequently faces challenges osmotic dynamics, which gives rise to pressure (a physical force). Osmotic overloading can crack integrity damage the REB. endurance of REB forces remains obscure. LMO7 (LIM domain only 7) is a protein associated with cell-cell junctional complex cortical F-actin. Its upregulation was observed cells cultured under hypertonic conditions. predominantly distributed tubule cells. Hypertonic stimulation leads F-actin assembly stress fibers Hypertonic-isotonic alternation, as force pushing plasma membrane inward/outward, set disturbance applied test FAK signaling functioning maintaining integrity. depletion resulted loss sheet-cultured medium or hypertonic-isotonic alternation. Conversely, inhibition by PF-573228 led failure robust association responding stress. Epithelial against are involved assembling elaborately manages activation cells, demonstrated excessive present depleted NRK-52E when were exposed environment. Our data suggests that regulates responsible for disturbance.

Язык: Английский

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