The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis

Abstract

FAP48 was identified and cloned thanks to its interaction with FK506-binding proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of immunophilins that bind the macrolide immunosuppressant drugs FK506 and rapamycin. We have previously shown that FAP48 -FKBP complexes are dissociated by FK506 and rapamycin, suggesting that FAP48 is an endogenous ligand of FKBP. The present work describes the biochemical consequences of FAP48 overexpression, induced by the tetracycline analogue doxycycline, in an established cell line derived from Jurkat T cells. We report that overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506. We also show that the expression levels of argininosuccinate synthetase and the Myc antagonist Mxi1 are modified by overexpression of FAP48, suggesting that these proteins could be good candidates to mediate the antiproliferative effect of FAP48. FAP48 affects neither the calcineurin-dependent nuclear factor of activated T cells (NFAT)1 nor JNK͞p38-dependent pathways that mediate immunosuppression by FK506. However, contrary to FK506, which blocks IL2 synthesis, we observed that FAP48 -FKBP complexes increase IL2 production, thus revealing a previously uncharacterized aspect of the immunosuppressive mechanism of FK506.T he pharmacological actions of immunosuppressant drugs such as FK506 and rapamycin are mediated in the cell by intracellular proteins named FK506-binding proteins (FKBPs) belonging to the immunophilin family (reviewed in refs. 1-3).The main cytoplasmic FKBP isoform is FKBP12, which, in a complex with FK506, binds to and inhibits the phosphatase calcineurin (4-6). Subsequently, dephosphorylation and nuclear translocation of nuclear factor of activated T cells (NFAT)1 can no longer occur, leading to the inhibition of the transcription of the IL2 gene, IL2 being the major growth factor for T cells (reviewed in ref. 7). In addition, a recent report has demonstrated that immunophilin-FK506 complexes block the JNK and p38 mitogen-activated protein kinases (MAPKs) during T cell activation and also inhibit IL2 synthesis via these pathways (8). The authors showed that direct inhibitors of calcineurin activity had no effect on JNK and p38 activation, suggesting that FK506 leads to immunosuppression via calcineurin-dependent as well as calcineurin-independent pathways.FKBP52 is another member of the FKBP family that was originally found associated with heat shock protein with a molecular mass of 90 kDa (HSP90) in the heterooligomeric forms of steroid receptor complexes (9, 10). FKBP52 displays a modular organization (11-13) and only the NH 2 -terminal part of the protein is responsible for the immunophilin character of the whole protein; it binds FK506 and rapamycin and displays a peptidylprolyl isomerase function characteristic of the immunophilin family (14). Although this NH 2 -terminal part shares high structural and functional homologies with FKBP12, it does not inhibit the phosphatase activity of calc...

Krüppel-Like Factor 2, a Novel Immediate-Early Transcriptional Factor, Regulates IL-2 Expression in T Lymphocyte Activation

“…Additionally, KLF2 increases IL-2 expression. Similar results were shown with FK506-binding proteinassociated protein FAP48, which not only inhibits Jurkat T cell proliferation, but also increases IL-2 synthesis in PHA/PMA-activated Jurkat T cells (35). KLF2 appears to act similarly to FK506-binding protein in T cell activation.…”

The Immunophilin-Interacting Protein AtFIP37 from Arabidopsis Is Essential for Plant Development and Is Involved in Trichome Endoreduplication

“…The initial analysis of AtFIP37 protein sequence indicated a weak identity (20%) with FAP48, a mammalian FKBP12 and FKBP59-associated protein (Chambraud et al, 1996), which has an antiproliferative action and plays a role in T cell activation (Krummrei et al, 2003). Recently, we observed that two animal proteins, HsWTAP and DmFL(2)D, were found to share stronger identities with AtFIP37 (Fig.…”

Transcriptional Profiling of Human Hematopoiesis During In Vitro Lineage‐Specific Differentiation

“…FAP 48 (FKBP-associated protein, 48 kDa) is essential for normal development of the vascular system and has an antiproliferative effect on Daisy T cells [40]. The candidate tumor suppressor gene MXI1 (Max-interacting protein 1) negatively regulates Myc oncoprotein activity and is upregulated by overexpression of FAP48 [40].…”

“…During erythropoietic differentiation, genes associated with the proto-oncogene c-myc are continuously downregulated, including Mina53 (myc-induced nuclear antigen with a molecular mass of 53 kDa), which is involved in cell proliferation and is directly induced by c-myc [38,39]. FAP 48 (FKBP-associated protein, 48 kDa) is essential for normal development of the vascular system and has an antiproliferative effect on Daisy T cells [40]. The candidate tumor suppressor gene MXI1 (Max-interacting protein 1) negatively regulates Myc oncoprotein activity and is upregulated by overexpression of FAP48 [40].…”