Alternative titles; symbols
HGNC Approved Gene Symbol: FKBP8
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:18,531,763-18,543,573 (from NCBI)
For background information on FK506-binding proteins (FKBPs), see FKBP1A (186945).
By PCR using Jurkat cell cDNA and degenerate oligonucleotides based on conserved regions of FKBPs, Lam et al. (1995) identified a cDNA encoding FKBP8. The deduced 355-amino acid protein shares 26 to 28% sequence identity with other known human FKBPs. FKBP8 contains an N-terminal domain that is 33% identical to that of FKBP12 (FKBP1A; 186945), a putative leucine zipper domain, a 3-unit imperfect tetratricopeptide repeat (TPR) domain, and a putative calmodulin-binding domain. Northern blot analysis detected a single, approximately 1.35- to 2.4-kb FKBP8 transcript in all human tissues examined, with the highest expression in brain.
Nielsen et al. (2004) presented evidence that the transcript encoding the deduced 38-kD FKBP8 protein identified by Lam et al. (1995) is truncated. By 5-prime RACE of adult mouse brain cDNA, they cloned transcripts produced by utilizing alternate first exons that encode 402- and 422-amino acid proteins with calculated molecular masses of 44 and 46 kD, respectively. The longer protein contains an N-terminal N-myristoylation site. EST database analysis identified a human transcript encoding a deduced 413-amino acid protein with an apparent molecular mass of 45 kD.
Nielsen et al. (2004) determined that the FKBP8 gene contains 10 exons and spans about 12 kb. The mouse Fkbp8 gene, which spans more than 11 kb, has a structure identical to that of the human gene except that it has 3 alternate first exons, designated 1a, 1b, and 1c. The first exon of the human FKBP8 gene is homologous to mouse exon 1a. Sequences in the exon 1a region are highly similar in mouse and human, and they are GC rich with consensus CCAAT boxes and several binding sites for Sp1 (189906), AP2 (107580), MZF1 (194550), and IK2.
Nielsen et al. (2004) stated that the FKBP8 gene is located on chromosome 19p12. They identified a polyadenylated pseudogene, which shares 89% identity with FKBP8, located in the intronic region between exons 10 and 11 of the PPP1R12B gene (603768) on chromosome 1q32.
Stumpf (2021) mapped the FKBP8 gene to chromosome 19p13.11 based on an alignment of the FKBP8 sequence (GenBank AY278607) with the genomic sequence (GRCh38).
FKBPs are intracellular receptors for the immunosuppressive drug FK506. The FKBP/FK506 complex exerts its immunosuppressive effects by inhibiting calcineurin (e.g., PPP3CA; 114105), a calcium- and calmodulin (e.g., CALM1; 114180)-dependent serine/threonine phosphatase that functions as a critical signaling molecule during T-cell activation. Using several human and mouse cell lines and expression constructs, Shirane and Nakayama (2003) found that FKBP8, unlike FKBP12, bound to and inhibited calcineurin even in the absence of FK506, suggesting that FKBP8 is an inherent inhibitor of calcineurin. FKBP8 associated with BCL2 (151430) and BCLXL (600039) in immunoprecipitation assays and colocalized with these proteins in mitochondria. The expression of mutant FKBP8 proteins induced redistribution of BCL2 and BCLXL. Overexpression of FKBP8 blocked apoptosis, whereas functional inhibition of FKBP8 by a dominant-negative mutant or by RNA interference promoted apoptosis. Shirane and Nakayama (2003) suggested that FKBP8 may inhibit apoptosis by anchoring BCL2 and BCLXL to mitochondrial membranes.
Presenilin-1 (PSEN1; 104311) and -2 (PSEN2; 600759) are mutated in some forms of familial Alzheimer disease (FAD; see 607822 and 606889, respectively). Wang et al. (2005) demonstrated that FKBP8 interacts with PSEN1 and PSEN2 by forming macromolecular complexes together with BCL2. Presenilins promoted degradation of FKBP8 and BCL2 and sequestered these proteins in the ER/Golgi compartments, thereby inhibiting FKBP8-mediated mitochondrial targeting of BCL2 via a gamma-secretase-independent mechanism. Thus, presenilins increased susceptibility to apoptosis by antagonizing the antiapoptotic function of FKBP8. In contrast, C-terminal fragments of caspase-processed PSEN1 and PSEN2 redistributed BCL2 to the mitochondria by abrogating the activity of full-length PSEN1 and PSEN2, resulting in a dominant-negative antiapoptotic effect. In cultured cells and mutant PSEN1-knockin mouse brains, FAD-linked presenilin mutants enhanced proapoptotic activity by causing a more efficient reduction in mitochondrial BCL2 than wildtype presenilins. Wang et al. (2005) suggested a novel molecular mechanism for the regulation of mitochondria-mediated apoptosis by competition between PSEN1/PSEN2 and FKBP8 for subcellular targeting of BCL2. Excessive proapoptotic activity of PSEN1/PSEN2 may play a role in the pathogenesis of FAD.
The mammalian target of rapamycin, mTOR (601231), is a central regulator of cell growth. Its activity is regulated by RHEB (601293), a Ras-like small GTPase, in response to growth factor stimulation and nutrient availability. Bai et al. (2007) showed that RHEB regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12 (186945). FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. RHEB interacts directly with FKBP38 and prevents its association with mTOR in a GTP-dependent manner. Bai et al. (2007) concluded that their findings suggested that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by RHEB in response to growth factor stimulation and nutrient availability.
Associations Pending Confirmation
In 472 bloodspot-derived DNA samples from newborns with lumbar spina bifida (see 182940) and 565 controls, Tian et al. (2020) sequenced the FKBP8 gene and detected 5 rare variants in the spina bifida patients and none in the controls. The FKBP8 variants included 1 nonsense mutation (E140X) and 4 missense mutations (S3L, K315N, A292S, and A251G), all of which occurred at highly conserved residues. Functional analysis demonstrated that the E140X variant affected FKBP8 localization to the mitochondria, as well as created a truncated protein form with impaired interaction with BCL2, resulting in an increase in cellular apoptosis. The S3L, K315N, and A292S variants decreased the FKBP8 protein level, whereas the K315N variant further increased cellular apoptosis. The authors concluded that functional variants of FKBP8 are risk factors for spina bifida.
Unlike previous Fkbp8-null mouse mutants, the Fkbp8-null mice created by Wong et al. (2008) showed posterior neural tube defects typical of spina bifida but survived up to 5 months of age. At embryonic day (E) 18.5, all mutant fetuses presented with isolated spina bifida spanning the thoracic and lumbar regions. Fkbp8-null mutants later developed splayed hind limbs and lower body paralysis due to severe bone and cartilage defects of the axial skeleton, including fused vertebrae. Loss of Fkbp8 resulted in increased apoptosis in the posterior neural tube. Microarray analysis revealed abnormal expression and patterning of genes expressed in the spinal cord. The phenotype of Fkbp8-null mutants appeared to be due, in part, to diminished expression of Zic1 (600470) in the dorsal neural tube and somites.
Tian et al. (2020) sequenced RNA from anterior and posterior tissue from Fkbp8 -/- and wildtype embryos at E9.5 and E10.5, and observed that Fkbp8-null embryos had an abnormal expression profile within tissues harvested at posterior sites. Gene ontology analysis revealed that the differentially expressed genes of the posterior embryo were primarily enriched for genes in the cell fate commitment pathway, axon genesis, and other neurodevelopment-related pathways. Two of the most significantly differentially expressed genes during the early stage of neural tube development were Wnt3a (606359) and Nkx2.9 (603245), suggesting that they may contribute to caudal-specific neural tube defects.
Bai, X., Ma, D., Liu, A., Shen, X., Wang, Q. J., Liu, Y., Jiang, Y. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318: 977-980, 2007. [PubMed: 17991864] [Full Text: https://doi.org/10.1126/science.1147379]
Lam, E., Martin, M., Wiederrecht, G. Isolation of a cDNA encoding a novel human FK506-binding protein homolog containing leucine zipper and tetratricopeptide repeat motifs. Gene 160: 297-302, 1995. [PubMed: 7543869] [Full Text: https://doi.org/10.1016/0378-1119(95)00216-s]
Nielsen, J. V., Mitchelmore, C., Pedersen, K. M., Kjaerulff, K. M., Finsen, B., Jensen, N. A. Fkbp8: novel isoforms, genomic organization, and characterization of a forebrain promoter in transgenic mice. Genomics 83: 181-192, 2004. [PubMed: 14667822] [Full Text: https://doi.org/10.1016/j.ygeno.2003.07.001]
Shirane, M., Nakayama, K. I. Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nature Cell Biol. 5: 28-37, 2003. [PubMed: 12510191] [Full Text: https://doi.org/10.1038/ncb894]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/20/2021.
Tian, T., Cao, X., Kim, S.-E., Lin, Y. L., Steele, J. W., Cabrera, R. M., Karki, M., Yang, W., Marini, N. J., Hoffman, E. N., Han, X., Hu, C., Wang, L., Wlodarczyk, B. J., Shaw, G. M., Ren, A., Finnell, R. H., Lei, Y. FKBP8 variants are risk factors for spina bifida. Hum. Molec. Genet. 29: 3132-3144, 2020. [PubMed: 32969478] [Full Text: https://doi.org/10.1093/hmg/ddaa211]
Wang, H.-Q., Nakaya, Y., Du, Z., Yamane, T., Shirane, M., Kudo, T., Takeda, M., Takebayashi, K., Noda, Y., Nakayama, K. I., Nishimura, M. Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. Hum. Molec. Genet. 14: 1889-1902, 2005. [PubMed: 15905180] [Full Text: https://doi.org/10.1093/hmg/ddi195]
Wong, R. L. Y., Wlodarczyk, B. J., Min, K. S., Scott, M. L., Kartiko, S., Yu, W., Merriweather, M. Y., Vogel, P., Zambrowicz, B. P., Finnell, R. H. Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube. Hum. Molec. Genet. 17: 587-601, 2008. [PubMed: 18003640] [Full Text: https://doi.org/10.1093/hmg/ddm333]