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Gene Review

SERPINB9  -  serpin peptidase inhibitor, clade B...

Homo sapiens

Synonyms: CAP-3, CAP3, Cytoplasmic antiproteinase 3, PI-9, PI9, ...
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Disease relevance of SERPINB9

  • SERPINB9 is the only known human intracellular inhibitor of granzyme B (GrB), the effector molecule in immunity against cytomegalovirus (CMV) and in renal allograft rejection [1].
  • We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these numbers with clinical outcome [2].
  • Purified recombinant PI9 failed to inhibit the amidolytic activities of trypsin, papain, thrombin, or Staphylococcus aureus endoproteinase Glu-C and did not form an SDS-stable complex when incubated with thrombin [3].
  • In addition, the reactive center loop of PI9 exhibits 54% identity with residues found in the reactive center loop of the cowpox virus CrmA serpin [3].
  • To investigated if PI-9 is important in the response to ASI, paraffin-embedded tissues from stage III or IV melanoma patients were stained [4].

High impact information on SERPINB9

  • We report here that the serine proteinase inhibitor (serpin) PI-9 accounts for the endogenous caspase-1 inhibitory activity in human SMCs and prevents processing of the enzyme's natural substrates, IL-1beta and IL-18 precursor [5].
  • In this study, the impact of PI-9 and bcl-2 expression on the sensitivity of lymphomas to T- and natural killer (NK) cell-mediated cytotoxicity was analyzed [6].
  • All lymphoma cells were sensitive to cytolysis by specific T cells and cytokine-activated NK cells, and no difference in sensitivity was observed with respect to PI-9 or bcl-2 expression [6].
  • We found PI-9 expression in 10 of 18 lymphoma cell lines and in 9 of 14 primary lymphomas [6].
  • Actual execution of apoptosis depends on proper functioning of effector caspases, particularly caspase 3, and on the expression levels of apoptosis-regulating proteins, including Bcl-2 and the recently identified granzyme B- specific protease inhibitor 9 (PI9) [2].

Chemical compound and disease context of SERPINB9


Biological context of SERPINB9


Anatomical context of SERPINB9

  • PI-9 should therefore be found in cytotoxic lymphocyte and bystander cell nuclei to ensure complete protection against graB [10].
  • Here we demonstrate by microscopy and subcellular fractionation experiments that PI-9 is present in the nuclei of human cytotoxic cells, endothelial cells, and epithelial cells [10].
  • Proteinase inhibitor 9 (PI-9) is a human serpin present in the cytoplasm of cytotoxic lymphocytes and epithelial cells [10].
  • Because dendritic cells (DCs) acquire characteristics similar to those of target cells to activate naive CD8(+) T cells and therefore may also require protection against grB, we investigated the expression of PI-9 in DCs [13].
  • PI-9 is up-regulated in response to grB production and degranulation, and associates with grB-containing granules in activated CTLs and NK cells [13].

Associations of SERPINB9 with chemical compounds

  • Furthermore, PI-9 is exported from nuclei via a leptomycin B-sensitive pathway, implying involvement of the export factor Crm1p [10].
  • Inhibition occurred with an overall K(i)' of 221 pM and a second-order association rate constant of 1.5 x 10(5) M(-1) s(-1), indicating that PI9 is a potent inhibitor of this serine proteinase in vitro [11].
  • Western blot analysis showed that estrogen strongly increases PI-9 protein levels [12].
  • Mutational inactivation of three potential imperfect estrogen response elements in the PI-9 5'-flanking region had no effect on moxestrol estrogen receptor induction [12].
  • Estrogens induced PI-9 mRNA within 2 h, PI-9 mRNA levels reached a plateau of 30-40-fold induction in 4 h, and induction was not blocked by cycloheximide, indicating that induction of PI-9 mRNA is a primary response [12].

Regulatory relationships of SERPINB9

  • These results suggest that PI-9 serves to inactivate misdirected granzyme B following cytotoxic cell degranulation [14].
  • Furthermore, PI-9 is expressed in monocyte-derived DCs and is up-regulated upon TNF-alpha-induced maturation of monocyte-derived DCs [13].

Other interactions of SERPINB9

  • PI6 and PI9 are almost identical in structure to the ovalbumin serpin genes at 18q21 [9].
  • The two novel serpins encoded by the two novel cDNA sequences have been designated as proteinase inhibitor 8 (PI8) and proteinase inhibitor 9 (PI9) [3].
  • We conclude that the nucleocytoplasmic distribution of PI-9 and related serpins involves a nonconventional nuclear import pathway and Crm1p [10].
  • In this report, we describe the inhibition of human neutrophil elastase by recombinant human PI9 [11].
  • The role of CAP3 in CD95 signaling: new insights into the mechanism of procaspase-8 activation [15].

Analytical, diagnostic and therapeutic context of SERPINB9

  • Therefore, using specific enzyme-linked immunosorbent assays, we addressed the presence of circulating SERPINB9 during primary CMV infection, subclinical rejection, acute rejection, and uncomplicated posttransplantation course [1].
  • PI9 was purified to homogeneity from the yeast cell lysate by a combination of heparin-agarose chromatography and Mono Q fast protein liquid chromatography and migrated as a single band in SDS-polyacrylamide gel electrophoresis with an apparent molecular mass of 42 kDa [3].
  • RESULTS: PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival [4].
  • Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy [4].
  • The granzyme B inhibitor SERPINB9 (protease inhibitor 9) circulates in blood and increases on primary cytomegalovirus infection after renal transplantation [1].


  1. The granzyme B inhibitor SERPINB9 (protease inhibitor 9) circulates in blood and increases on primary cytomegalovirus infection after renal transplantation. Rowshani, A.T., Strik, M.C., Molenaar, R., Yong, S.L., Wolbink, A.M., Bemelman, F.J., Hack, C.E., Ten Berge, I.J. J. Infect. Dis. (2005) [Pubmed]
  2. Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. ten Berge, R.L., Meijer, C.J., Dukers, D.F., Kummer, J.A., Bladergroen, B.A., Vos, W., Hack, C.E., Ossenkoppele, G.J., Oudejans, J.J. Blood (2002) [Pubmed]
  3. Molecular cloning, expression, and partial characterization of two novel members of the ovalbumin family of serine proteinase inhibitors. Sprecher, C.A., Morgenstern, K.A., Mathewes, S., Dahlen, J.R., Schrader, S.K., Foster, D.C., Kisiel, W. J. Biol. Chem. (1995) [Pubmed]
  4. Expression of the apoptosis inhibitor protease inhibitor 9 predicts clinical outcome in vaccinated patients with stage III and IV melanoma. van Houdt, I.S., Oudejans, J.J., van den Eertwegh, A.J., Baars, A., Vos, W., Bladergroen, B.A., Rimoldi, D., Muris, J.J., Hooijberg, E., Gundy, C.M., Meijer, C.J., Kummer, J.A. Clin. Cancer Res. (2005) [Pubmed]
  5. The serpin proteinase inhibitor 9 is an endogenous inhibitor of interleukin 1beta-converting enzyme (caspase-1) activity in human vascular smooth muscle cells. Young, J.L., Sukhova, G.K., Foster, D., Kisiel, W., Libby, P., Schönbeck, U. J. Exp. Med. (2000) [Pubmed]
  6. Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2. Godal, R., Keilholz, U., Uharek, L., Letsch, A., Asemissen, A.M., Busse, A., Na, I.K., Thiel, E., Scheibenbogen, C. Blood (2006) [Pubmed]
  7. The C-terminal 26-residue peptide of serpin A1 is an inhibitor of HIV-1. Congote, L.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  8. Chemotherapy for advanced head and neck cancer with the combination adriamycin, cyclophosphamide, and cis-diamminedichloroplatinum (II): preliminary assessment of a one-day vs. three-day drug regimen. Creagan, E.T., Fleming, T.R., Edmonson, J.H., Ingle, J.N., Woods, J.E. Cancer (1981) [Pubmed]
  9. A serpin gene cluster on human chromosome 6p25 contains PI6, PI9 and ELANH2 which have a common structure almost identical to the 18q21 ovalbumin serpin genes. Sun, J., Stephens, R., Mirza, G., Kanai, H., Ragoussis, J., Bird, P.I. Cytogenet. Cell Genet. (1998) [Pubmed]
  10. Nucleocytoplasmic distribution of the ovalbumin serpin PI-9 requires a nonconventional nuclear import pathway and the export factor Crm1. Bird, C.H., Blink, E.J., Hirst, C.E., Buzza, M.S., Steele, P.M., Sun, J., Jans, D.A., Bird, P.I. Mol. Cell. Biol. (2001) [Pubmed]
  11. Inhibition of neutrophil elastase by recombinant human proteinase inhibitor 9. Dahlen, J.R., Foster, D.C., Kisiel, W. Biochim. Biophys. Acta (1999) [Pubmed]
  12. Proteinase inhibitor 9, an inhibitor of granzyme B-mediated apoptosis, is a primary estrogen-inducible gene in human liver cells. Kanamori, H., Krieg, S., Mao, C., Di Pippo, V.A., Wang, S., Zajchowski, D.A., Shapiro, D.J. J. Biol. Chem. (2000) [Pubmed]
  13. The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. Hirst, C.E., Buzza, M.S., Bird, C.H., Warren, H.S., Cameron, P.U., Zhang, M., Ashton-Rickardt, P.G., Bird, P.I. J. Immunol. (2003) [Pubmed]
  14. A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. Sun, J., Bird, C.H., Sutton, V., McDonald, L., Coughlin, P.B., De Jong, T.A., Trapani, J.A., Bird, P.I. J. Biol. Chem. (1996) [Pubmed]
  15. The role of CAP3 in CD95 signaling: new insights into the mechanism of procaspase-8 activation. Golks, A., Brenner, D., Schmitz, I., Watzl, C., Krueger, A., Krammer, P.H., Lavrik, I.N. Cell Death Differ. (2006) [Pubmed]
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