Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A.

Price, Edmund; Jin, Mingjie; Lim, Do-Seon; Pati, S.; Walsh, Christopher T.; McKeon, Frank

doi:10.1073/pnas.91.9.3931

Cited by 113 publications

(120 citation statements)

References 52 publications

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“…Cyp B contains N-terminal signal sequence (21), is produced in endoplasmic reticulum, and is secreted into biological fluids such as milk and plasma (34,35). Spik and his colleagues demonstrated that peripheral blood T lymphocytes possess binding sites of Cyp B that internalize extracellular Cyp B into cells (36).…”

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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“…Two of those, namely Cyp18 and Cyp23, belong to the cyclophilin family of PPIases. As Cyp18 was preferably found in the cytoplasm and the nucleus (Marks et al, 1991) whereas Cyp23 resides in the endoplasmic reticulum (Price et al, 1994), we focused our further analysis on potential Cyp18-p53 interactions. CoIP experiments revealed a Cyp18 association with p53 in both the cytoplasmic and nuclear fractions as shown by LC-ESI-MS/MS analysis ( Figure 1a, sections a and b).…”

Section: Physical Association Of P53 With Cyp18mentioning

confidence: 99%

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

et al. 2009

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The functional diversity of the tumor suppressor protein p53 is mainly regulated by protein interactions. In this study, we describe a new interaction with the peptidylprolyl cis/trans isomerase cyclophilin 18 (Cyp18). The interaction reduced the sequence-specific DNA binding of p53 in vitro, whereas the inhibition of the interaction increased p53-reporter gene activity in vivo. The active site of the folding helper enzyme Cyp18 was directly involved in binding. The proline-rich region (amino acids 64-91) of p53 was most likely responsible for the observed binding because a synthetic peptide comprising amino acids 68-81 of p53 inhibited this interaction, and a p53 variant containing a proline residue at position 72 (p53 P72 ) interacted with Cyp18 more effectively than the corresponding p53 R72 variant. Impairment of the Cyp18-p53 interaction induced an accumulation of cells in the G2/M phase of the cell cycle, which was more pronounced when p53 P72 was expressed compared with p53 R72 in an otherwise isogenic cellular background. Moreover, p53-dependent apoptosis was elevated in Cyp18 knockout cells, suggesting an antiapoptotic potential of Cyp18-p53 complexes. Functional in vivo data hint to a possible clinical relevance of the p53-Cyp18 interaction observed.

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“…CypB is a member of the larger immunophilin family of cis-trans peptidyl-prolyl isomerases, which also includes the FK506 binding proteins and target of rapamycin (Tor) (25). CypB has been observed in the ER and nucleus and can be found in appreciable levels in blood (150 ng͞ml) and breast milk (26,27). Whereas its role as a chaperone in protein transport through the ER (28) or as a costimulatory molecule for T lymphocytes (29) has been speculated upon, the exact function of CypB has remained uncertain.…”

mentioning

confidence: 99%

The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer

Rycyzyn

Clevenger

2002

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

140

124

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The nuclear translocation of peptide hormones, such as the somatolactogenic hormone prolactin, after receptor internalization has been widely reported. Prolactin has been demonstrated to interact with cyclophilin B, a member of the immunophilin family of proteins. Cyclophilin B interaction with prolactin potentiated prolactin-induced proliferation, cell growth, and the nuclear retrotransport of prolactin. These effects could be abrogated by the removal of the peptidyl-prolyl isomerase activity of cyclophilin B. Our findings indicate that the intranuclear prolactin͞cyclophilin B complex acts as a transcriptional inducer by interacting directly with Stat5, resulting in the removal of the Stat-repressor protein inhibitor of activated Stat 3 (PIAS3), thereby enhancing Stat5 DNA-binding activity and prolactin-induced, Stat5-mediated gene expression.T he pleiotropic actions of the somatolactogenic hormone prolactin (PRL) are mediated by signaling through the prolactin receptor, a member of the type I family of cytokine receptors (1-3). Upon ligand binding and dimerization of the receptor, several signaling cascades are activated, including Ras-Raf, Fyn-Vav and Jak2-Stat5 (4-7). Activated Jak2 phosphorylates Stat5 on tyrosine residues, inducing Stat5 dimerization and translocation to the nucleus (8). Intranuclear Stat5 binds to consensus Stat5 response elements, resulting in the transactivation of numerous PRL-specific genes, of which ␤-casein is the most extensively studied (9). This Stat5 transcriptional activation can be cooperatively enhanced by the glucocorticoid receptor (GR) and C͞EBP␤ (10-12).While the above-mentioned pathways are all associated with PRL-induced signaling, activation of the PRL receptor is also associated with ligand internalization via an endosomal-like pathway across the endoplasmic reticulum (ER) and nuclear envelopes (13,14). The phenomenon of protein retrotransport was initially characterized through the study of retrotranslocated viral and bacterial proteins and peptides destined for presentation on the major histocompatibility complex (15-18). These studies revealed that protein retrotransport depends on transport through the protein-conducting channel formed by the Sec61 complex in the ER membrane. Electron microscopy studies employing colloidal gold-labeled PRL demonstrated that upon ligand internalization into endosomes, approximately 90% of the internalized PRL either remained within the endosome or was degraded. However, the remaining 10% was detected as passing from the endosome through multivesicular bodies and the Golgi͞ER to arrive in the nucleus within 2 h poststimulation (13). The functional significance of nuclear PRL was demonstrated by the finding that a nuclear-targeted construct of PRL containing the simian virus 40 large T antigen nuclear localization sequence provided a necessary comitogenic stimulus for IL-2-driven growth (19). The nuclear retrotransport and potential action of peptide hormones and growth factors is widespread, as epidermal growth factor, insulin, grow...

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Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A.

Cited by 113 publications

References 52 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

The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis

The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer

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