Caveolae Participate in Tumor Necrosis Factor Receptor 1 Signaling and Internalization in a Human Endothelial Cell Line

D’Alessio, Alessio; Al‐Lamki, Rafia S.; Bradley, John R.; Pober, Jordan S.

doi:10.1016/s0002-9440(10)62346-2

Cited by 105 publications

(106 citation statements)

References 42 publications

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“…Cultured ECs grown in static media internalize shed TNFR1 ectodomains (56). However, in an in situ assay that we believe to be novel, we failed to detect any evidence for endothelial internalization of the TNFR1 ectodomains, although our assay successfully detected albumin internalization, thereby ruling out nonspecific errors.…”

Section: Figurementioning

confidence: 58%

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

et al. 2011

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Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca 2+ , and the purinergic receptor P 2 Y 2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca 2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca 2+ -dependent increase of mitochondrial H 2 O 2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.

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Section: Figurementioning

confidence: 58%

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

et al. 2011

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“…Considering that high concentrations of peroxynitrite can induce pathophysiological processes such as apoptosis (5,47), that signaling molecules involved in regulating pro-and antisurvival signaling pathways related to oxidative stress are concentrated in membrane rafts (61), and that the TNF-␣ receptor and associated factors can also localize to cholesterolenriched microdomains (8,12,32), the localization of nitrotyrosine-containing proteins in rafts/caveolae may also partially explain the mechanism by which TNF-␣ induces apoptosis. This concept is supported by the observation that cholesterol depletion can mitigate TNF-␣-induced apoptosis (12,32).…”

Section: Discussionmentioning

confidence: 99%

TNF-α potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells

Yang

Rizzo²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Yang B, Rizzo V. TNF-␣ potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 292: H954 -H962, 2007. First published October 6, 2006; doi:10.1152/ajpheart.00758.2006.-A major source of reactive oxygen species (ROS) in endothelial cells is the NADPH oxidase enzyme complex. The selective distributions of any enzyme within cells have important implications in regulating enzyme effectiveness through facilitation of access to local substrates and/or product targets. Because membrane rafts provide a spatially preferable environment for a variety of enzyme systems, we sought to determine whether NADPH oxidase is present and functional in this plasma membrane compartment in endothelial cells. We found that, in resting endothelial cells, NADPH oxidase subunits were preassembled and the enzyme functional in membrane rafts, specifically in caveolae. Stimulation with TNF-␣ induced additional recruitment of the p47 phox regulatory subunit to raft-localized NADPH oxidase and enhanced ROS production within raft domains. TNF-␣ also induced nitric oxide production through activation of endothelial nitric oxide synthase (eNOS) present in the same membrane compartment. The dual activation of superoxide and nitric oxide-generating systems provided a spatially favorable environment for nitration of tyrosine-containing proteins localized to rafts. Perturbation of membrane raft structural integrity with cholesterol-sequestering compounds caused the delocalization of NADPH oxidase subunits and eNOS from the rafts and inhibited TNF-␣-induced ROS production and protein tyrosine nitration. Together, these data provide evidence that membrane rafts and caveolae play a role in the spatial regulation of NADPH oxidase and subsequent ROS/reactive nitrogen species in endothelial cells. lipid rafts; endothelial nitric oxide synthase; reactive oxygen species SUPEROXIDE AND hydrogen peroxide (H 2 O 2 ) generated within vascular cells can either promote dysfunction or mediate normal cellular processes. This apparent paradox may be explained by the type and quantity of the oxidant produced in the cell. In addition, the subcellular positioning of oxidant-producing enzyme systems may provide a mechanism that allows products to access local targets. Therefore, the spatial generation of superoxide and H 2 O 2 is likely to be a key factor in determining differential responses to similar reactive oxygen species (ROS) produced within the cell. Because endothelial cells generate superoxide and H 2 O 2 in response to a variety of proatherogenic stimuli, including cytokines and oscillatory shear stress (18,36,43,55), the local distribution of ROSgenerating enzyme systems may be relevant to understanding endothelial cell responses during atherogenesis.Although several enzymes have been reported to endogenously release ROS within the endothelium, the major source of ROS appears to be the NADPH oxidase enzyme complex. Best desc...

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“…Besides the EGF and insulin receptors, the regulation by Cav-1 of different receptors signaling pathways, such as tumor necrosis factor receptor 1 and transforming growth factor ␤, some of them implicated in the process of liver regeneration, has been described recently. 39,40 In summary, we have studied the role of Cav-1 in liver regeneration after PH and in liver cell lines under proinflammatory stimulation. Our results show an increase in Cav-1 in the early phase of liver regeneration with a translocation of the protein to the noncaveolar fraction; however, Cav-1 is dispensable for liver regeneration, and its role in the process deserves further work.…”

Section: Discussionmentioning

confidence: 99%

Dispensability and dynamics of caveolin-1 during liver regeneration and in isolated hepatic cells

et al. 2007

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C aveolae were originally identified with an electron microscope as flask-shaped membrane invaginations on the surface of epithelial 1 and endothelial cells. 2 These plasmalemmal vesicles are enriched in sphingolipids, cholesterol, and caveolin (Cav), the major protein constituent of these structures. 3 Three Cavs have been identified in differentiated cells with specific patterns of distribution. Cav-1 and Cav-2 are found in adipocytes and endothelial cells, 4 whereas Cav-3 is selectively expressed in muscle cells. 5 Caveolae participate in many cellular processes, including vesicular transport, 6 cholesterol homeostasis, 7 regulation of signal transduction, 8 integrin signaling, 9 and cell growth. 10 Despite this, it is rather surprising that all Cav-null mice are viable, including the complete caveola-less mouse; however, the combined loss of Cav-1 and Cav-3 has profound effects on the cardiovascular function. 11 Caveolae have now been demonstrated to concentrate a wide variety of signaling molecules, including Src family tyrosine kinases, H-Ras, heterotrimeric G protein ␣ subunits, protein kinase C isoforms, and endothelial nitric oxide synthase (NOS; i.e., NOS-3). 12 Many signaling molecules directly interact with Cav-1 through a defined modular protein domain, which is known as the Cavscaffolding domain. The Cav-scaffolding domain has been shown to directly inhibit the activation of NOS-3, 13 epidermal growth factor receptor, 14 and c-neu 15 among other molecules. Moreover, Cav-1 is a potent inhibitor of proliferative pathways such as the Ras-p42/p44 MAP (mitogen activated protein kinase) kinase cascades. 16 Cav-1 expression negatively regulates cell cycle progression through a p53/p21-dependent pathway, 17 and several cellular oncoproteins down-regulate Cav-1 expression. 10

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Caveolae Participate in Tumor Necrosis Factor Receptor 1 Signaling and Internalization in a Human Endothelial Cell Line

Cited by 105 publications

References 42 publications

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

TNF-α potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells

Dispensability and dynamics of caveolin-1 during liver regeneration and in isolated hepatic cells

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