Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics

Yurchenko, Vyacheslav; Constant, Stephanie L.; Eisenmesser, Elan; Bukrinsky, Michael

doi:10.1111/j.1365-2249.2010.04115.x

Cited by 214 publications

(252 citation statements)

References 155 publications

(218 reference statements)

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“…BSG and NPTN bind S100A9 and cyclophilins A and B and up-regulate the expression of matrix metalloproteinase (17,32) to promote cancer-cell metastasis. BSG also laterally interacts with various proteins such as cyclophilin 60, integrins, monocarboxylate transporter 1 (MCT1), γ-secretase, and glucose transporter 1 (Glut1) (17).…”

Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

117

130

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Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG −/− NPTN −/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG's association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.phospholipid scramblase | Xkr8 | chaperone | basigin | neuroplastin P hospholipids are asymmetrically distributed in plasma membranes by flippases that actively translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine from the outer to inner leaflets of the membrane (1, 2). This asymmetrical distribution is disrupted in the activated platelets and apoptotic cells (3), in which the PtdSer exposed on the cell surface serves as a scaffold for blood clotting factors and as an "eat me" signal, respectively (4, 5). ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6, 7). Two processes, flippase inactivation and scramblase activation, must occur to disrupt the asymmetrical phospholipid distribution and expose PtdSer on the cell surface (8).Scramblases are membrane proteins that nonspecifically and bidirectionally transport phospholipids between the two plasma membrane leaflets (9). Ca 2+ -activated phospholipid scrambling is mediated by membrane proteins that belong to the transmembrane protein (TMEM)16 (also called ANO) family (8). Of 10 human TMEM16-family members, 5 are Ca 2+ -activated phospholipid scramblases at plasma membranes. TMEM16F exposes PtdSer in activated platelets and osteoblasts (10-12). The tertiary structure of fungal TMEM16 and the biochemical characterization of mouse TMEM16 family members indicate that TMEM16 forms a homodimer that directly binds Ca 2+ (13).Phospholipid scrambling and PtdSer exposure in apoptotic cells is mediated by another family of membrane proteins, the XK-related (Xkr) proteins (8). Of 10 human Xkr family members, Xkr8 (ubiquitously expressed) and Xkr4 and Xkr9 (expressed in specific tissues) are cleaved by caspase during apoptosis to expose PtdSer (14, 15), but how the cleavage activates these Xkrs to scramble phospholipids is unknown. XK, the founding member of the Xkr family, associates with Kell, a type II membrane protein (16). Whether Xkr8 and other Xkr-family members associate with other proteins has not been addressed.In this report, we found that...

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Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

117

130

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“…CD147 is a type I transmembrane glycoprotein, a member of the immunoglobulin super-family, that is expressed by a wide array of cell types, including epithelial, endothelial and hematopoietic cells (6). CD147 is a signaling receptor for extracellular cyclophilins (Cyp) A and B (7,8), and recent publications have identified the CD147 signaling pathway induced by extracellular cyclophilins as a triggering mechanism regulating MMP expression and inflammation in atherosclerosis, rheumatoid arthritis, allergic and chronic lung disease (9)(10)(11)(12)(13)(14).…”

Section: Targeting Extracellular Cyclophilins Ameliorates Disease Promentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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“…EMMPRIN wird nicht nur auf Tumorzellen exprimiert, sondern kommt vor allem auch auf Zellen des hämatopo-etischen Systems sowie in Epithel-und Endothelzellen vor [16].…”

Section: Struktur Und Expressionunclassified