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Optineurin links Hace1-dependent Rac ubiquitylation 1 to integrin-mediated mechanotransduction to control bacterial invasion and cell divisionOptineurin links Hace1-dependent Rac ubiquitylation 1 to integrin-mediated mechanotransduction to control bacterial invasion and cell division

ABSTRACT: Extracellular matrix (ECM) elasticity is perceived by cells via focal adhesion structures, which transduce mechanical cues into chemical signaling to conform cell behavior. Although the contribution of ECM compliance to the control of cell migration or division has been extensively studied, little has been reported regarding whole proteome adaptation to changes of mechanical forces. Uropathogenic E. coli (UPEC) are responsible of 70-95% of the Urinary Tract Infections (UTIs), comprising cystitis, prostatitis and pyelonephritis. These are recurrent or chronic infections causing significant costs in public health. UPEC produce the Cytotoxic Necrotizing Factor1 (CNF1) toxin, targeting one of the major host mechano-sensor and -adaptor, namely the actin cytoskeleton. We have discovered that the CNF1 and integrin-dependent invasion of cells by UPEC is highly dependent on ECM stiffness. Here we aim to analyze primary human cells treated or not with CNF1 and cultured on a fibronectin ECM of variable stiffness by label free shotgun proteomics, to bring new concepts on the manipulation of host tissue mechanics by pathogens.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Endothelial Cell Of Vascular Tree

SUBMITTER: Delphi Van Haver

LAB HEAD: Amel Mettouchi

PROVIDER: PXD035396 | Pride | 2022-10-25

REPOSITORIES: Pride

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RAP2 Mediates Mechanotransduction to Hippo pathway

Project description:Mammalian cells are surrounded by the extracellular matrix (ECM), which regulates intercellular signal transduction and provides structural support to cells. Mechanical forces generated by ECM play a key role in regulating cell behaviors including survival, growth, mobility, and differentiation. However, it is unclear how mechanical forces are sensed by cells and transmit biochemical signals to cell fate-determining transcription factors such as YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif). Here we show the identification of Ras-associated protein 2 (RAP2) as an intracellular signal transducer that senses ECM rigidity and modulates cell survival and growth by negatively regulating YAP/TAZ. Activation of RAP2 by low ECM stiffness or contact inhibition triggers YAP/TAZ phosphorylation. Deletion of RAP2 leads to sustained YAP/TAZ activation in cells that grow on soft matrix or undergo contact inhibition, alters transcription programs initiated by low matrix stiffness, and results in cell transformation and malignant growth. Mechanistically, RAP2 can directly bind to Mitogen-activated protein kinase kinase kinase kinase 4/6/7 (MAP4K4/6/7) or Rho GTPase activating protein 29 (ARHGAP29), both of which lead to LATS1/2 activation and YAP/TAZ inhibition. These findings define a new molecular pathway that transmits mechanical cues to their effectors in the nucleus.

2018-07-09 | GSE98547 | GEO

Key role for Rac in the early transcriptional response to ECM stiffness and the stiffness-dependent repression of ATF3

Project description:The Rho family GTPases, Rac and Rho, play critical roles in transmitting mechanical information contained within the extracellular matrix (ECM) to the cell. Rac and Rho have well described roles in regulating stiffness-dependent actin remodeling, proliferation and motility. However, much less is known about the relative roles of these GTPases in stiffness-dependent transcription, particularly at the genome-wide level. Here, we selectively inhibited Rac and Rho in mouse embryonic fibroblasts cultured on deformable substrata and used RNA sequencing to elucidate and compare the contribution of these GTPases to the early transcriptional response to ECM stiffness. Surprisingly, we found that the stiffness-dependent activation of Rac is dominant over Rho in the initial transcriptional response to ECM stiffness. We also identified Activating Transcription Factor 3 (ATF3) as a major target of stiffness/Rac-mediated signaling and show that ATF3 repression by ECM stiffness helps to explain how the stiffness-dependent activation of Rac results in the induction of cyclin D1.

2023-10-04 | GSE236266 | GEO

Extracellular matrix (ECM) stiffness and collagen-1 (col-1) responsive genes in 3D cultured mammary epithelial cells

Project description:We report the expression profiles of MCF10A cells encapsulated in hydrogels of varying stiffness and composition. Cells were encapsulated for 7 days in either 1.) soft alginate and reconstituted basement membrane (rBM), 2.) stiff alginate and rBM, 3,) soft col-1 and rBM, or 4.) stiff col-1. We find global gene expression changes in response to enhanced ECM stiffness, independent of expression changes in response to col-1 exposure. These results provide a comprehensive study of the gene expression changes associated with increased ECM stiffness in addition to the gene expression changes associated with increased col-1 concentration in combination with, and independent of, ECM stiffness.

2019-03-25 | GSE102506 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [RNA-seq]

Project description:Oligodendrocytes are the primary producers of many extracellular matrix (ECM) related proteins found in the central nervous system (CNS), thereby, these cells play a critical role in the determination of brain stiffness, node of Ranvier formation, perinodal ECM deposition and perineuronal net formation. The transcription factors that control ECM related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte specific ablation of Sp7 changes ECM composition and brain stiffness, and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggests that Sp7 plays a conserved biological role in oligodendrocytes and in bone forming cells, where it mediates brain and bone tissue stiffness by controlling the expression of ECM components.

2023-09-11 | GSE221192 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

2023-09-11 | GSE221191 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ATAC-seq]

2023-09-11 | GSE221189 | GEO

Proteomes of uropathogenic Escherichia coli growing in human urine and in J82 urinary bladder cell.

Project description:Uropathogenic Escherichia coli (UPEC) are the most common cause of urinary tract infection (UTI). UPEC normally reside in the intestine, and during establishment of UTI, it undergoes metabolic adaptations, first to urine and then upon tissue invasion to the bladder cell interior. In order to understand these adaptations, we used quantitative proteomic profiling to characterize protein expression of UPEC strain UTI89 growing in human urine and when inside J82 bladder cells. In order to facilitate detection of UPEC proteins over the excess amount of eukaryotic proteins in bladder cells, we developed a method where proteins from UTI89 grown in MOPS and urine was spiked-in to enhance detection of bacterial proteins. More than 2000 E. coli proteins were detected. During growth in urine, proteins associated with iron acquisition and several amino acid uptake and biosynthesis systems, in particular arginine metabolism, were significantly upregulated. During growth in J82 cells, proteins related to iron uptake and arginine metabolisms were upregulated together with proteins involved in sulphur compound turnover. Results suggested that UPEC experience a richer environment in bladder cells compared to urine. There was no direct correlation between upregulated proteins and proteins reported to be essential for infections, showing that upregulation during growth does not signify that the proteins are essential for growth under a condition.

2022-06-09 | PXD032049 | Pride

Mining the stiffness-sensitive transcriptome in human vascular smooth muscle cells identifies long non-coding RNA stiffness regulators

Project description:Vascular extracellular matrix (ECM) stiffening is a risk factor for aortic and coronary artery disease. How matrix stiffening regulates the transcriptome profile of human aortic (Ao) and coronary (Co) vascular smooth muscle cells (VSMCs) is not well understood. Furthermore, the role of long non-coding RNAs (lncRNAs) in the cellular response to stiffening has never been explored. This study characterizes the stiffness-sensitive transcriptome of human Ao and Co VSMCs and identify potentially key lncRNA regulators of stiffness-dependent VSMC functions. Ao and Co VSMCs were cultured on hydrogel substrates mimicking physiologic and pathologic ECM stiffness. Total RNA-seq was performed to compare the stiffness-sensitive transcriptome profiles of Ao and Co VSMCs.

2017-12-01 | GSE100081 | GEO

Murine chondrocytes cells：stiff gel vs. the soft gel

Project description:Transcriptional profiling of mouse chondrocytes cells comparing control untreated chondrocytes cells with chondrocytes cells plated in stiff and soft ECM. Goal was to determine the effects of ECM stiffness on gene expression.

2016-07-26 | GSE63615 | GEO

Caveolin-1 modulates mechanotransduction responses to substrate stiffness through actin-dependent control of YAP

Project description:The transcriptional regulator YAP orchestrates important cell functions, determining tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin cytoskeleton-dependent and Hippo kinase-independent mechanisms. RHO activity is necessary but not sufficient for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based siRNA screenings provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective ECM remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications.

2018-10-16 | GSE120514 | GEO

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