FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology

Yasuda‐Yamahara, Mako; Rogg, Manuel; Frimmel, J.; Trachte, Philipp; Helmstaedter, Martin; Schröder, Patricia; Schiffer, Mario; Schell, Christoph; Huber, Tobias B.

doi:10.1016/j.matbio.2018.01.003

Cited by 29 publications

(20 citation statements)

References 49 publications

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“…Here, we show that elimination of integrins in FCs results in an increase in cortical F-actin and a reduction in the density of stress fibers specifically on the basal side of FCs 30 . Results from cell culture experiments have led to the proposal that the interplay between cell-ECM adhesion, actomyosin contractility and cortical actin cytoskeleton define cell morphology.…”

Section: Resultsmentioning

confidence: 66%

Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks

Mateos

Valencia-Expósito

Míguez

et al. 2019

Preprint

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29Forces generated by the actomyosin cytoskeleton are key contributors to the 30 generation of tissue shape. Within the cell, the actomyosin cytoskeleton organizes in 31 different types of networks, each of them performing distinct roles. In addition, 32 although they normally localize to precise regions of the cells, they are rarely 33 independent and often their dynamics influence each other. In fact, the reorganization of 34 a given structure can promote the formation of another, conversions that govern many 35 morphogenetic processes. In addition, maintenance of a specific actomyosin network 36 organization in a differentiated tissue might be equally important. Failure to do so could 37 lead to undesired cell state transitions, which in turn would have drastic consequences 38 on the homeostasis of the tissue. Still, little is known about the mechanisms that ensure 39 controlled transitions between actomyosin networks during morphogenesis or their 40 maintenance in a differentiated tissue. Here, we use the Drosophila follicular epithelium 41 to show that cell-ECM interactions mediated by integrins are necessary for the 42 establishment and maintenance of the different actomyosin networks present in these 43 epithelial cells. Elimination of integrins in a group of follicle cells results in changes in 44 the F-actin levels and physical properties of their intracellular actomyosin networks. 45Integrin mutant follicle cells have reduced number of basal stress fibers. They also show 46 increased cortical F-actin levels and tension, which interferes with proper basal surface 47 growth. Finally, clonal elimination of integrins also triggers non-autonomous 48 behavioural changes in neighbouring wild types cells, which now reorganize their actin 49 cytoskeleton and spread and overlay the mutant ones. Based on these results, we 50propose that cell-ECM interactions mediated by integrins regulate epithelia 51 morphogenesis and homesostasis by preserving the different types of intracellular actin 52 networks. 53 54 55 56 57 58 59 60 61 62 Forces generated by F-actin networks are important contributors to the generation of 64 cell and tissue shape. The architecture and mechanical properties of the F-actin network 65 are modulated by myosin II motors and actin binding proteins (reviewed in 1 . The 66 molecular composition of contractile actin networks and bundles is highly conserved 67 among eukaryotic species 2 . Nevertheless, their organization and dynamics change 68 across different cell types, their position within the cell and the differentiation state of 69 the cell. 70 There are two main ways in which actomyosin networks can be organized within 71 the cell, as cortical two-dimensional meshworks below the plasma membrane or as 72 stress-fibers. Studies over the last decade have assigned distinct roles for these two 73 types of networks. Thus, while pulsatile contraction of cortical actomyosin meshworks 74 has been mainly implicated in the cell shape changes underlying key morphogenetic 75 processes, such as gastrulatio...

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Section: Resultsmentioning

confidence: 66%

Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks

Mateos

Valencia-Expósito

Míguez

et al. 2019

Preprint

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“…The CRISPR/Cas9 genome editing technology was used to generate AIF1L KO podocytes as described before [ 11 ]. gRNAs were designed targeting exon 4 or exon 5 of the human AIF1L gene (e-crisp.org— http://www.e-crisp.org/E-CRISP/ ) (gRNAs: , ).…”

Section: Methodsmentioning

confidence: 99%

“…Given the prominent localization on the outer surface of glomerular capillaries podocytes essentially rely on a fine controlled adhesion system via specialized complexes commonly termed as focal adhesion [ 2 ]. We and others have shown that components of this complex not only fulfill pure mechanical functions, but are also involved in complex signaling cascades determining intracellular processes and cell shape control [ 8 – 11 ]. Despite growing knowledge about relevant components of the podocyte cytoskeleton [ 5 ], we are far from a complete understanding how specific proteins determine podocyte function and morphology on a spatial and temporal level.…”

Section: Introductionmentioning

confidence: 99%

AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes

et al. 2018

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Podocytes are highly-specialized epithelial cells essentially required for the generation and the maintenance of the kidney filtration barrier. This elementary function is directly based on an elaborated cytoskeletal apparatus establishing a complex network of primary and secondary processes. Here, we identify the actin-bundling protein allograft-inflammatory-inhibitor 1 like (AIF1L) as a selectively expressed podocyte protein in vivo. We describe the distinct subcellular localization of AIF1L to actin stress fibers, focal adhesion complexes and the nuclear compartment of podocytes in vitro. Genetic deletion of AIF1L in immortalized human podocytes resulted in an increased formation of filopodial extensions and decreased actomyosin contractility. By the use of SILAC based quantitative proteomics analysis we describe the podocyte specific AIF1L interactome and identify several components of the actomyosin machinery such as MYL9 and UNC45A as potential AIF1L interaction partners. Together, these findings indicate an involvement of AIF1L in the stabilization of podocyte morphology by titrating actomyosin contractility and membrane dynamics.

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“…In contrast to the microarray data, Rho GTPase-activating protein 6 (Arhgap6) and the Rho GTPase (Rhod) did not differ in their RNA content between Ahr +/and Ahr -/-DETC; they were almost undetectable. Expression of fermitin family member 2 (Fermt2), whose product is also called Kindlin-2, and is known to link actin-structures to podocyte morphology [41], was strongly down-regulated in Ahr -/-DETC. In T cells the related protein Kindlin-3 has been shown to coordinate F-actin, which enables integrin-signaling and migration [42].…”

Section: Detc Of Ahr -/-Mice Are Inflammatory Active and Have Alteredmentioning

confidence: 99%

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

Merches

Schiavi

Weighardt

et al. 2020

IJMS

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Background Aryl hydrocarbon receptor (AHR)-deficient mice do not support the expansion of dendritic epidermal T cells (DETC), a resident immune cell population in the murine epidermis, which immigrates from the fetal thymus to the skin around birth. Material and Methods In order to identify the gene expression changes underlying the DETC disappearance in AHR-deficient mice, we analyzed microarray RNA-profiles of DETC, sorted from the skin of two-week-old AHR-deficient mice and their heterozygous littermates. In vitro studies were done for verification, and IL-10, AHR repressor (AHRR), and c-Kit deficient mice analyzed for DETC frequency. Results We identified 434 annotated differentially expressed genes. Gene set enrichment analysis demonstrated that the expression of genes related to proliferation, ion homeostasis and morphology differed between the two mouse genotypes. Importantly, with 1767 pathways the cluster-group “inflammation” contained the majority of AHR-dependently regulated pathways. The most abundant cluster of differentially expressed genes was “inflammation.” DETC of AHR-deficient mice were inflammatory active and had altered calcium and F-actin levels. Extending the study to the AHRR, an enigmatic modulator of AHR-activity, we found approximately 50% less DETC in AHRR-deficient mice than in wild-type-littermates. Conclusion AHR-signaling in DETC dampens their inflammatory default potential and supports their homeostasis in the skin.

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FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology

Cited by 29 publications

References 49 publications

Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks

Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks

AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

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