Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINB9
Cytogenetic location: 6p25.2 Genomic coordinates (GRCh38): 6:2,887,270-2,903,309 (from NCBI)
PI9 belongs to the large superfamily of serine proteinase inhibitors (serpins), which bind to and inactivate serine proteinases. These interactions are involved in many cellular processes, including coagulation, fibrinolysis, complement fixation, matrix remodeling, and apoptosis (Sprecher et al., 1995).
Sprecher et al. (1995) isolated PI8 (601697) and PI9 cDNAs from a human placenta cDNA library. PI9 encodes a 374-amino acid polypeptide that shares more than 60% identity with PI6 (173321). Northern blot analysis detected 2 PI9 transcripts of 3.4 and 4.4 kb that were most abundant in lung and placenta.
In searching for serpins related to PI6, Sun et al. (1996) isolated and cloned PI9 from human bone marrow mRNA using a PCR cloning strategy. They confirmed that the sequence of PI9 is closely related to PI6 and the viral serpin CrmA. Sun et al. (1996) observed that PI9 was expressed in immune tissue, including lymphocytes, natural killer cell leukemia cell lines, and peripheral blood mononuclear cells. Fractionation experiments showed that PI9 is localized to the cytosol, in a separate subcellular compartment from granzyme B (123910), with which it forms a complex.
By immunohistochemical and Western blot analyses, Bladergroen et al. (2001) demonstrated cytoplasmic expression of the 42-kD PI9 protein in dendritic cell populations, but not macrophage populations, of lymphoid organs. B- and T-cell populations were variably positive in different lymphoid organs, and only endothelial cells expressed PI9 in nonlymphoid organs. Notably, PI9 expression was high in immunologically privileged sites, such as eye lens, testis, ovary, and placenta. Bladergroen et al. (2001) concluded that PI9 expression patterns are distinct from those of other OVA serpins, such as PI6 and PAI2 (173390). They proposed that PI9 expression may be important for resistance to granzyme B-induced apoptosis, preserving vessel integrity, and maintaining immune privilege.
Sun et al. (1996) showed that PI9 forms an SDS-resistant complex with granzyme B, suggesting that these 2 proteins may form a physiologically significant serpin-serine proteinase interaction.
PI9 was identified as an endogenous inhibitor of caspase-1 (147678). Krieg et al. (2001) reported that PI9 mRNA and protein are rapidly and directly induced by estrogen in human liver cells. Using transient transfections to assay PI9 promoter truncations and mutations, they showed that this strong estrogen induction is mediated by a unique downstream estrogen responsive unit (ERU) approximately 200 nucleotides downstream of the transcription start site. They also demonstrated estrogen-dependent binding of ER to the cellular PI9 promoter. The ERU consists of an imperfect estrogen response element (ERE) palindrome immediately adjacent to a direct repeat containing two consensus ERE half-sites separated by 13 nucleotides (DR13). In transient transfections, all 4 of the ERE half-sites in the imperfect ERE and in the DR13 were important for estrogen inducibility. They concluded that a direct repeat can function with an imperfect ERE palindrome to confer estrogen inducibility on a native gene, which extends the repertoire of DNA sequences able to function as EREs.
Barrie et al. (2004) noted that virally infected hepatocytes resist cytotoxic T-lymphocyte (CTL) or natural killer (NK) killing by perforin (PRF1; 170280)- and granzyme-dependent cytotoxic effector pathways by expressing PI9 or its murine homolog, Spi6. Instead, FAS (TNFRSF6; 134637)- and TNFR (see 191190)-mediated apoptosis are more prominent in killing virally infected liver cells. Using immunoblot analysis, Barrie et al. (2004) found that PI9 and Spi6 were not detectable in uninfected hepatocytes, and PI9 was detected only at low levels in human hepatoma cells. In vivo adenoviral infection or in vitro exposure to IFNA (IFNA1; 147660)/IFNB (IFNB1; 147640) or IFNG (147570) induced Spi6 expression in murine hepatocytes. IFNA, IFNG, and TNF (191160) all upregulated expression of PI9, but not PI8, in human hepatoma cells. Barrie et al. (2004) concluded that cytokines that promote antiviral cytopathic responses also regulate expression of cytoprotective PI9 in hepatocytes that are potential targets of CTL and NK effector mechanisms.
Eyre et al. (1996) used fluorescence in situ hybridization to map PI9 to chromosome 6p25. They noted that there is a cluster of serpins at this chromosomal location that includes PI6 and ELANH2 (see 130135).
Barrie, M. B., Stout, H. W., Abougergi, M. S., Miller, B. C., Thiele, D. L. Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6. J. Immun. 172: 6453-6459, 2004. [PubMed: 15128837] [Full Text: https://doi.org/10.4049/jimmunol.172.10.6453]
Bladergroen, B. A., Strik, M. C. M., Bovenschen, N., van Berkum, O., Scheffer, G. L., Meijer, C. J. L. M., Hack, C. E., Kummer, J. A. The granzyme B inhibitor, protease inhibitor 9, is mainly expressed by dendritic cells and at immune-privileged sites. J. Immun. 166: 3218-3225, 2001. [PubMed: 11207275] [Full Text: https://doi.org/10.4049/jimmunol.166.5.3218]
Eyre, H. J., Sun, J., Sutherland, G. R., Bird, P. Chromosomal mapping of the gene (PI9) encoding the intracellular serpin proteinase inhibitor 9 to 6p25 by fluorescence in situ hybridization. Genomics 37: 406-408, 1996. [PubMed: 8938458] [Full Text: https://doi.org/10.1006/geno.1996.0580]
Krieg, S. A., Krieg, A. J., Shapiro, D. J. A unique downstream estrogen responsive unit mediates estrogen induction of proteinase inhibitor-9, a cellular inhibitor of IL-1-beta-converting enzyme (caspase 1). Molec. Endocr. 15: 1971-1982, 2001. [PubMed: 11682627] [Full Text: https://doi.org/10.1210/mend.15.11.0719]
Sprecher, C. A., Morgenstern, K. A., Mathewes, S., Dahlen, J. R., Schrader, S. K., Foster, D. C., Kisiel, W. Molecular cloning, expression, and partial characterization of two novel members of the ovalbumin family of serine proteinase inhibitors. J. Biol. Chem. 270: 29854-29861, 1995. [PubMed: 8530382] [Full Text: https://doi.org/10.1074/jbc.270.50.29854]
Sun, J., Bird, C. H., Sutton, V., McDonald, L., Coughlin, P. B., De Jong, T. A., Trapani, J. A., Bird, P. I. A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. J. Biol. Chem. 271: 27802-27809, 1996. [PubMed: 8910377] [Full Text: https://doi.org/10.1074/jbc.271.44.27802]