Two Distinct Regions of Cyclophilin B Are Involved in the Recognition of a Functional Receptor and of Glycosaminoglycans on T Lymphocytes

Carpentier, Mathieu; Allain, Fabrice; Haendler, Bernard; Denys, A; Mariller, Christophe; Benaı̈ssa, Monique; Spik, Geneviève

doi:10.1074/jbc.274.16.10990

Cited by 31 publications

(70 citation statements)

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“…Spik and his colleagues demonstrated that peripheral blood T lymphocytes possess binding sites of Cyp B that internalize extracellular Cyp B into cells (36). To date, the fate and the function of internalized Cyp B are not clear.…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of Cyclophilin B and Caspase-Activated Deoxyribonuclease in the Induction of Chromosomal DNA Degradation in TCR-Stimulated Thymocytes

Nagata¹,

Kishi²,

Liu³

et al. 2000

The Journal of Immunology

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TCR engagement of immature CD4+CD8+ thymocytes induces clonal maturation (positive selection) as well as clonal deletion (negative selection) in the thymus. However, the cell death execution events of thymocytes during the negative selection process remain obscure. Using a cell-free system, we identified two different DNase activities in the cytosol of in vivo anti-TCR-stimulated murine thymocytes: one that induced chromosomal DNA fragmentation, which was inhibited by an inhibitor of caspase-activated DNase, and another that induced plasmid DNA degradation, which was not inhibited by an inhibitor of caspase-activated DNase. We purified the protein to homogeneity that induced plasmid DNA degradation from the cytosol of anti-CD3-stimulated thymocytes and found that it is identical with cyclophilin B (Cyp B), which was reported to locate in endoplasmic reticulum. Ab against Cyp B specifically inhibited the DNA degradation activity in the cytosol of anti-CD3-stimulated thymocytes. Furthermore, recombinant Cyp B induced DNA degradation of naked nuclei, but did not induce internucleosomal DNA fragmentation. Finally, we demonstrated that TCR engagement of a murine T cell line (EL4) with anti-CD3/CD28 resulted in the release of Cyp B from the microsome fraction to the cytosol/nuclear fraction. Our data strongly suggest that both active caspase-activated DNase and Cyp B may participate in the induction of chromosomal DNA degradation during cell death execution of TCR-stimulated thymocytes.

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Section: Discussionmentioning

confidence: 99%

Possible Involvement of Cyclophilin B and Caspase-Activated Deoxyribonuclease in the Induction of Chromosomal DNA Degradation in TCR-Stimulated Thymocytes

Nagata¹,

Kishi²,

Liu³

et al. 2000

The Journal of Immunology

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“…The central core is highly conserved between both cyclophilin isoforms, making CyPA a putative ligand for the CyPB type I site. Conversely, the binding region to GAGs was located in the N-terminal extension of CyPB and we clearly identified the sequences 3 KKK 5 and 15 YFD 17 as absolutely required for this interaction (27). CyPA does not possess these clusters, explaining why CyPB is a unique, highly specific ligand for type II site.…”

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confidence: 91%

“…CyPA does not possess these clusters, explaining why CyPB is a unique, highly specific ligand for type II site. The binding regions of CyPB are located on opposite sides of the molecule, suggesting that proteoglycan-bound ligand is presented to functional receptors (27). Such a mechanism might account for differences in the biological responses triggered by CyPA and CyPB.…”

mentioning

confidence: 99%

“…In our hands, however, CyPA was unable to compete with surface-bound radio-labeled CyPB, which may reflect either the existence of two distinct receptors or a large difference in binding affinities for the same receptor. Most recently, we demonstrated that surface binding of CyPB involved two classes of sites (26,27). The first class, termed type I, was identified as a specific functional receptor, whereas the second class, termed type II, was identified as sulfated glycosaminoglycans (GAGs) of the heparan sulfate family (26).…”

mentioning

confidence: 99%

“…The first class, termed type I, was identified as a specific functional receptor, whereas the second class, termed type II, was identified as sulfated glycosaminoglycans (GAGs) of the heparan sulfate family (26). The location of binding regions in CyPB was delineated by engineering mutated proteins (27). Interaction with type I site involved the central conserved core of CyPB, which shares CsA-binding and catalytic domains, and can consequently be inhibited by CsA.…”

mentioning

confidence: 99%

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Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix

Allain

Vanpouille

Carpentier

et al. 2002

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

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119

156

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Cyclophilins A and B (CyPA and CyPB) are cyclosporin A-binding proteins that are involved in inflammatory events. We have reported that CyPB interacts with two types of cell-surface-binding sites. The first site corresponds to a functional receptor and requires interaction with the central core of CyPB. This region is highly conserved in cyclophilins, suggesting that CyPA and CyPB might share biological activities mediated by interaction with this receptor. The second site is identified with glycosaminoglycans (GAGs), the binding region located in the N terminus of CyPB. The difference in the N-terminal extensions of CyPA and CyPB suggests that a unique interaction with GAGs might account for selective activity of CyPB. To explore this hypothesis, we analyzed the lymphocyte responses triggered by CyPA, CyPB, and CyPB KKK؊, a mutant unable to interact with GAGs. The three ligands seemed capable enough to elicit calcium signal and chemotaxis by binding to the same signaling receptor. In contrast, only CyPB enhanced firm adhesion of T cells to the extracellular matrix. This activity depended on the interactions with GAGs and signaling receptor. CyPB-mediated adhesion required CD147 presumably because it was a costimulatory molecule and was related to an activation of ␣4␤1 and ␣4␤7 integrins. Finally, we showed that CyPB was capable mainly to enhance T cell adhesion of the CD4 ؉ CD45RO ؉ subset. The present data indicate that CyPB rather than CyPA is a proinflammatory factor for T lymphocytes and highlight the crucial role of CyPB-GAG interaction in the chemokine-like activity of this protein.

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Participation of 3‐O‐sulfated heparan sulfates in the protection of macrophages by herpes simplex virus‐1 glycoprotein D and cyclophilin B against apoptosis

et al. 2016

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Heparan sulfates (HS) are involved in numerous biological processes, which rely on their ability to interact with a large panel of proteins. Although the reaction of 3‐O‐sulfation can be catalysed by the largest family of HS sulfotransferases, very few mechanisms have been associated with this modification and to date, only glycoprotein D (gD) of herpes simplex virus‐1 (HSV‐1 gD) and cyclophilin B (CyPB) have been well‐described as ligands for 3‐ O ‐sulfated HS. Here, we hypothesized that both ligands could induce the same responses via a mechanism dependent on 3‐ O ‐sulfated HS. First, we checked that HSV‐1 gD was as efficient as CyPB to induce the activation of the same signalling events in primary macrophages. We then demonstrated that both ligands efficiently reduced staurosporin‐induced apoptosis and modulated the expression of apoptotic genes. In addition to 3‐ O ‐sulfated HS, HSV‐1 gD was reported to interact with other receptors, including herpes virus entry mediator (HVEM), nectin‐1 and ‐2. Thus, we decided to identify the contribution of each binding site in the responses triggered by HSV‐1 gD and CyPB. We found that knock‐down of 3‐ O ‐sulfotransferase 2, which is the main 3‐ O ‐sulfated HS‐generating enzyme in macrophages, strongly reduced the responses induced by both ligands. Moreover, silencing the expression of HVEM rendered macrophages unresponsive to either HSV‐1 gD and CyPB, thus indicating that both proteins induced the same responses by interacting with a complex formed by 3‐ O ‐sulfated HS and HVEM. Collectively, our results suggest that HSV‐1 might hijack the binding sites for CyPB in order to protect macrophages against apoptosis for efficient infection.

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Two Distinct Regions of Cyclophilin B Are Involved in the Recognition of a Functional Receptor and of Glycosaminoglycans on T Lymphocytes

Abstract: Cyclophilin B is a cyclosporin

Cited by 31 publications

References 45 publications

Possible Involvement of Cyclophilin B and Caspase-Activated Deoxyribonuclease in the Induction of Chromosomal DNA Degradation in TCR-Stimulated Thymocytes

Possible Involvement of Cyclophilin B and Caspase-Activated Deoxyribonuclease in the Induction of Chromosomal DNA Degradation in TCR-Stimulated Thymocytes

Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix

Participation of 3‐O‐sulfated heparan sulfates in the protection of macrophages by herpes simplex virus‐1 glycoprotein D and cyclophilin B against apoptosis

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