A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress

Acharya, Bipul R.; Nestor-Bergmann, Alexander; Liang, Xuan; Budnar, Srikanth; Jensen, Oliver E.; Bryant, Zev; Yap, Alpha

doi:10.1101/281154

Cited by 42 publications

(72 citation statements)

References 48 publications

(46 reference statements)

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“…RhoA activation in turn stimulates Rho‐associated protein kinase (ROCK). Activated ROCK induces F‐actin polymerization . RhoA also activates PKN1/2 kinase, which phosphorylates the pyrin inflammasome at S205 and S241.…”

Section: Mechanotransduction‐associated Kinases In Inflammasome Signamentioning

confidence: 99%

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Joshi

Morley

2019

Journal of Leukocyte Biology

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Many intracellular signals, such as host danger-associated molecules and bacterial toxins during infection, elicit inflammasome activation. However, the mechanical environment in tissues may also influence the sensitivity of various inflammasomes to activation. The cellular mechanical environment is determined by the extracellular tissue stiffness, or its inverse, tissue compliance. Tissue stiffness is sensed by the intracellular cytoskeleton through a process termed mechanotransduction. Thus, extracellular compliance and the intracellular cytoskeleton may regulate the sensitivity of inflammasome activation. Control of proinflammatory signaling by tissue compliance may contribute to the pathogenesis of diseases such as ventilator-induced lung injury during bacterial pneumonia and tissue fibrosis in inflammatory disorders. The responsible signaling cascades in inflammasome activation pathways and mechanotransduction crosstalk are not yet fully understood. This rather different immunomodulatory perspective will be reviewed and open questions discussed here. K E Y W O R D S cell adhesion, inflammasome, inflammation, integrins, mechanobiology, monocytes/macrophages

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Section: Mechanotransduction‐associated Kinases In Inflammasome Signamentioning

confidence: 99%

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Joshi

Morley

2019

Journal of Leukocyte Biology

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“…In this context, it is interesting to note the marked parallels between regulation of tight junction and adherens junction integrity. These include junctional tensile stress (tight junction - [125]; adherens junction - [132]), localized RhoA activation (tight junction - [121]; adherens junction - [132]), p114RhoGEF activation (tight junction - [133]; adherens junction - [132]), Gα12 activation (albeit in opposite directions; tight junction - [134]; adherens junction - [132]), mDia1 organization of actin structures (tight junction and adherens junction - [135]), and a tension sensor which transitions between a closed and an open conformation that exposes protein binding sites (tight junction (ZO-1) - [136]; adherens junction (α-catenin) - [137]). These similarities could represent a convergent evolution of regulatory mechanisms for the two junctional structures or, alternatively, an overlap in the mechanisms regulating the two junctional structures.…”

Section: What Is the Leak Pathway?mentioning

confidence: 99%

The Leak Pathway: A Pathway in Flux

Monaco¹,

Ovryn²,

Axis³

et al. 2019

Preprint

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The epithelial cell tight junction structure is the site of the transepithelial movement of solutes and water between epithelial cells (paracellular permeability). Paracellular permeability can be divided into two distinct pathways, the Pore Pathway mediating the movement of small ions and solutes and the Leak Pathway mediating the movement of large solutes. Claudin proteins form the basic paracellular permeability barrier and mediate the movement of small ions and solutes via the Pore Pathway. The Leak Pathway remains less understood. Several proteins have been implicated in mediating the Leak Pathway, including occludin, ZO proteins, tricellulin, and actin filaments, but the proteins comprising the Leak Pathway remain unresolved. The properties of the Leak Pathway, such as its molecular mechanism, its regulation, and whether or not it has a potential size limit, remain controversial. This review will trace the evolution of the Leak Pathway concept from its origins, will discuss the current information about the properties of the Leak Pathway, and will discuss recent research suggesting a possible molecular basis for the Leak Pathway. Based on these findings, we propose a model for the molecular mechanism underlying the Leak Pathway and its regulation.

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“…Given the role of p114RhoGEF in the regulation of dynamic cellular processes and the coordination of actomyosin activation in response to changes in cell adhesion in vitro (Acharya et al, 2018;Haas et al, 2020;Nakajima and Tanoue, 2011;Terry et al, 2012;Terry et al, 2011;Zihni et al, 2017), we asked whether such functions are important for organ morphogenesis. Our data show that p114RhoGEF is indeed essential for mouse development with embryos displaying a number of different phenotypes.…”

Section: Introductionmentioning

confidence: 99%

ARHGEF18/p114RhoGEF coordinates PKA/CREB signaling and actomyosin remodeling to drive trophoblast cell-cell fusion during placenta morphogenesis

Beal

Fernandez

Grammatopoulos

et al. 2020

Preprint

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Coordination of cell-cell adhesion, actomyosin dynamics and gene expression is crucial for morphogenetic processes underlying tissue and organ development. Rho GTPases are main regulators of the cytoskeleton and adhesion. They are activated by guanine nucleotide exchange factors in a spatially and temporally controlled manner. However, the roles of these Rho GTPase activators during complex developmental processes are still poorly understood. ARHGEF18/p114RhoGEF is a tight junction-associated RhoA activator that forms complexes with myosin II, and regulates actomyosin contractility. Here we show that p114RhoGEF/ ARHGEF18 is required for mouse syncytiotrophoblast differentiation and placenta development. In vitro and in vivo experiments identify that p114RhoGEF controls expression of AKAP12, a protein regulating PKA signalling, and is required for PKA-induced actomyosin remodelling, CREB-driven gene expression of proteins required for trophoblast differentiation, and, hence, trophoblast cell-cell fusion. Our data thus indicate that p114RhoGEF links actomyosin dynamics and cell-cell junctions to PKA/CREB signalling, gene expression and cell-cell fusion.

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A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress

Abstract: A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress. AbstractAdherens junctions are tensile structures that couple epithelial cells together.

Cited by 42 publications

References 48 publications

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

The Leak Pathway: A Pathway in Flux

ARHGEF18/p114RhoGEF coordinates PKA/CREB signaling and actomyosin remodeling to drive trophoblast cell-cell fusion during placenta morphogenesis

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