| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
(Received for publication, June 5, 1996, and in revised form, August 7, 1996)
From the Department of Medicine, Using a polymerase chain reaction strategy we
identified a serine proteinase inhibitor (serpin) in human bone marrow
that is related to the cellular serpin proteinase inhibitor 6 (PI-6)
and the viral serpin cytokine response modifier A (CrmA). This serpin,
proteinase inhibitor 9 (PI-9), has an unusual reactive center
P1(Glu)-P1
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27802-27809
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
and
Cellular Cytotoxicity
Laboratory,
(Cys), which suggests that it
inhibits serine proteinases that cleave after acidic residues. The only
known serine proteinase with this specificity is granzyme B, a granule
cytotoxin produced by cytotoxic lymphocytes. To test the interaction of
PI-9 with granzyme B we prepared recombinant hexa-histidine tagged PI-9
in a yeast expression system. Addition of the recombinant protein to
native granzyme B resulted in an SDS-resistant complex typical of
serpin-serine proteinase interactions. Further analysis showed that
complex formation followed bimolecular kinetics with a second order
rate constant of 1.7 ± 0.3 × 106
M
1 s1, which is in the range
for a physiologically significant serpin-proteinase interaction.
Recombinant PI-9 also completely abrogated granzyme B and
perforin-mediated cytotoxicity in vitro. Examination of
PI-9 mRNA distribution demonstrated that it is expressed in immune
tissue, primarily in lymphocytes. The highest levels of PI-9 mRNA
and protein were observed in natural killer cell leukemia cell lines
and in interleukin-2 stimulated peripheral blood mononuclear cells,
which also produce granzyme B. Like PI-6, PI-9 was shown to be a
cytosolic protein that is not secreted. Fractionation of natural killer
cells and stimulated peripheral blood mononuclear cells demonstrated
that PI-9 is in a separate subcellular compartment to granzyme B. These
results suggest that PI-9 serves to inactivate misdirected granzyme B
following cytotoxic cell degranulation. This may explain why cytotoxic
cells are not damaged by their own granzyme B during destruction of
abnormal cells.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  K. A. Andrew, H. M. A. Simkins, S. Witzel, R. Perret, J. Hudson, I. F. Hermans, D. S. Ritchie, J. Yang, and F. Ronchese Dendritic Cells Treated with Lipopolysaccharide Up-Regulate Serine Protease Inhibitor 6 and Remain Sensitive to Killing by Cytotoxic T Lymphocytes In Vivo J. Immunol., December 15, 2008; 181(12): 8356 - 8362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Getachew, H. Stout-Delgado, B. C. Miller, and D. L. Thiele Granzyme C Supports Efficient CTL-Mediated Killing Late in Primary Alloimmune Responses J. Immunol., December 1, 2008; 181(11): 7810 - 7817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bots and J. P. Medema Serpins in T cell immunity J. Leukoc. Biol., November 1, 2008; 84(5): 1238 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tapia, L. M. Gangi, F. Zegers-Hochschild, J. Balmaceda, R. Pommer, L. Trejo, I. M. Pacheco, A. M. Salvatierra, S. Henriquez, M. Quezada, et al. Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy Hum. Reprod., February 1, 2008; 23(2): 340 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Montes-Moreno, G. Roncador, L. Maestre, N. Martinez, L. Sanchez-Verde, F. I. Camacho, J. Cannata, J. L. Martinez-Torrecuadrada, Y. Shen, W. C. Chan, et al. Gcet1 (centerin), a highly restricted marker for a subset of germinal center-derived lymphomas Blood, January 1, 2008; 111(1): 351 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. W. Stout-Delgado, Y. Getachew, B. C. Miller, and D. L. Thiele Intrahepatic Lymphocyte Expression of Dipeptidyl Peptidase I-Processed Granzyme B and Perforin Induces Hepatocyte Expression of Serine Proteinase Inhibitor 6 (Serpinb9/SPI-6) J. Immunol., November 15, 2007; 179(10): 6561 - 6567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhang, N. Liu, S.-M. Park, Y. Wang, S. Byrne, A. E. Murmann, S. Bahr, M. E. Peter, S. T. Olson, A. Belaaouaj, et al. Serine Protease Inhibitor 6-Deficient Mice Have Increased Neutrophil Immunity to Pseudomonas aeruginosa J. Immunol., October 1, 2007; 179(7): 4390 - 4396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kaiserman, C. H. Bird, J. Sun, A. Matthews, K. Ung, J. C. Whisstock, P. E. Thompson, J. A. Trapani, and P. I. Bird The major human and mouse granzymes are structurally and functionally divergent J. Cell Biol., November 20, 2006; 175(4): 619 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sipione, K. C. Simmen, S. J. Lord, B. Motyka, C. Ewen, I. Shostak, G. R. Rayat, J. M. Dufour, G. S. Korbutt, R. V. Rajotte, et al. Identification of a Novel Human Granzyme B Inhibitor Secreted by Cultured Sertoli Cells J. Immunol., October 15, 2006; 177(8): 5051 - 5058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Jahrsdorfer, S. E. Blackwell, J. E. Wooldridge, J. Huang, M. W. Andreski, L. S. Jacobus, C. M. Taylor, and G. J. Weiner B-chronic lymphocytic leukemia cells and other B cells can produce granzyme B and gain cytotoxic potential after interleukin-21-based activation Blood, October 15, 2006; 108(8): 2712 - 2719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hernandez-Pigeon, C. Jean, A. Charruyer, M.-J. Haure, M. Titeux, L. Tonasso, A. Quillet-Mary, C. Baudouin, M. Charveron, and G. Laurent Human Keratinocytes Acquire Cellular Cytotoxicity under UV-B Irradiation: IMPLICATION OF GRANZYME B AND PERFORIN J. Biol. Chem., May 12, 2006; 281(19): 13525 - 13532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laforge, N. Bidere, S. Carmona, A. Devocelle, B. Charpentier, and A. Senik Apoptotic Death Concurrent with CD3 Stimulation in Primary Human CD8+ T Lymphocytes: A Role for Endogenous Granzyme B J. Immunol., April 1, 2006; 176(7): 3966 - 3977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Kurschus, R. Bruno, E. Fellows, C. S. Falk, and D. E. Jenne Membrane receptors are not required to deliver granzyme B during killer cell attack Blood, March 1, 2005; 105(5): 2049 - 2058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Waterhouse, K. A. Sedelies, K. A. Browne, M. E. Wowk, A. Newbold, V. R. Sutton, C. J. P Clarke, J. Oliaro, R. K. Lindemann, P. I. Bird, et al. A Central Role for Bid in Granzyme B-induced Apoptosis J. Biol. Chem., February 11, 2005; 280(6): 4476 - 4482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bots, I. G. M. Kolfschoten, S. A. Bres, M. T. G. A. Rademaker, G. M. de Roo, M. Kruse, K. L. M. C. Franken, M. Hahne, C. J. Froelich, C. J. M. Melief, et al. SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity Blood, February 1, 2005; 105(3): 1153 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mahrus, W. Kisiel, and C. S. Craik Granzyme M Is a Regulatory Protease That Inactivates Proteinase Inhibitor 9, an Endogenous Inhibitor of Granzyme B J. Biol. Chem., December 24, 2004; 279(52): 54275 - 54282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.C. dos Santos, B. Han, C.F. Andrade, X. Bai, S. Uhlig, R. Hubmayr, M. Tsang, M. Lodyga, S. Keshavjee, A.S. Slutsky, et al. DNA microarray analysis of gene expression in alveolar epithelial cells in response to TNF{alpha}, LPS, and cyclic stretch Physiol Genomics, November 17, 2004; 19(3): 331 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Phillips, J. T. Opferman, R. Shah, N. Liu, C. J. Froelich, and P. G. Ashton-Rickardt A Role for the Granzyme B Inhibitor Serine Protease Inhibitor 6 in CD8+ Memory Cell Homeostasis J. Immunol., September 15, 2004; 173(6): 3801 - 3809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. N. Benning, J. C. Whisstock, J. Sun, P. I. Bird, and S. P. Bottomley The human serpin proteinase inhibitor-9 self-associates at physiological temperatures Protein Sci., July 1, 2004; 13(7): 1859 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Sedelies, T. J. Sayers, K. M. Edwards, W. Chen, D. G. Pellicci, D. I. Godfrey, and J. A. Trapani Discordant Regulation of Granzyme H and Granzyme B Expression in Human Lymphocytes J. Biol. Chem., June 18, 2004; 279(25): 26581 - 26587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Barrie, H. W. Stout, M. S. Abougergi, B. C. Miller, and D. L. Thiele Antiviral Cytokines Induce Hepatic Expression of the Granzyme B Inhibitors, Proteinase Inhibitor 9 and Serine Proteinase Inhibitor 6 J. Immunol., May 15, 2004; 172(10): 6453 - 6459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sun, C. H. Bird, K. Y. Thia, A. Y. Matthews, J. A. Trapani, and P. I. Bird Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity J. Biol. Chem., April 23, 2004; 279(17): 16907 - 16911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Pak, V. Kumar, C. Tsu, C. J. Luke, Y. S. Askew, D. J. Askew, D. R. Mills, D. Bromme, and G. A. Silverman SRP-2 Is a Cross-class Inhibitor That Participates in Postembryonic Development of the Nematode Caenorhabditis elegans: INITIAL CHARACTERIZATION OF THE CLADE L SERPINS J. Biol. Chem., April 9, 2004; 279(15): 15448 - 15459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Andrade, L. A. Casciola-Rosen, and A. Rosen A Novel Domain in Adenovirus L4-100K Is Required for Stable Binding and Efficient Inhibition of Human Granzyme B: Possible Interaction with a Species-Specific Exosite Mol. Cell. Biol., September 1, 2003; 23(17): 6315 - 6326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J J Oudejans, R L ten Berge, and C J L M Meijer Immune escape mechanisms in ALCL J. Clin. Pathol., June 1, 2003; 56(6): 423 - 425. [Full Text] [PDF]
|
|
|
|
|
|
C. E. Hirst, M. S. Buzza, C. H. Bird, H. S. Warren, P. U. Cameron, M. Zhang, P. G. Ashton-Rickardt, and P. I. Bird 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 J. Immunol., January 15, 2003; 170(2): 805 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kannan-Thulasiraman and D. J. Shapiro Modulators of Inflammation Use Nuclear Factor-kappa B and Activator Protein-1 Sites to Induce the Caspase-1 and Granzyme B Inhibitor, Proteinase Inhibitor 9 J. Biol. Chem., October 18, 2002; 277(43): 41230 - 41239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Korkmaz, S. Attucci, E. Hazouard, M. Ferrandiere, M. L. Jourdan, M. Brillard-Bourdet, L. Juliano, and F. Gauthier Discriminating between the Activities of Human Neutrophil Elastase and Proteinase 3 Using Serpin-derived Fluorogenic Substrates J. Biol. Chem., October 11, 2002; 277(42): 39074 - 39081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. N. Balaji, N. Schaschke, W. Machleidt, M. Catalfamo, and P. A. Henkart Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation J. Exp. Med., August 19, 2002; 196(4): 493 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Chipuk, L. V. Stewart, A. Ranieri, K. Song, and D. Danielpour Identification and Characterization of A Novel Rat Ov-Serpin Family Member, Trespin J. Biol. Chem., July 12, 2002; 277(29): 26412 - 26421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. ten Berge, C. J. L. M. Meijer, D. F. Dukers, J. A. Kummer, B. A. Bladergroen, W. Vos, C. E. Hack, G. J. Ossenkoppele, and J. J. Oudejans Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma Blood, May 29, 2002; 99(12): 4540 - 4546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Hamerman, F. Hayashi, L. A. Schroeder, S. P. Gygi, A. L. Haas, L. Hampson, P. Coughlin, R. Aebersold, and A. Aderem Serpin 2a Is Induced in Activated Macrophages and Conjugates to a Ubiquitin Homolog J. Immunol., March 1, 2002; 168(5): 2415 - 2423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Bladergroen, C. J. L. M. Meijer, R. L. ten Berge, C. E. Hack, J. J. F. Muris, D. F. Dukers, A. Chott, Y. Kazama, J. J. Oudejans, O. van Berkum, et al. Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system? Blood, January 1, 2002; 99(1): 232 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Hirst, M. S. Buzza, V. R. Sutton, J. A. Trapani, K. L. Loveland, and P. I. Bird Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction Mol. Hum. Reprod., December 1, 2001; 7(12): 1133 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Krieg, A. J. Krieg, and D. J. Shapiro A Unique Downstream Estrogen Responsive Unit Mediates Estrogen Induction of Proteinase Inhibitor-9, a Cellular Inhibitor of IL-1{beta}- Converting Enzyme (Caspase 1) Mol. Endocrinol., November 1, 2001; 15(11): 1971 - 1982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Medema, J. de Jong, L. T. C. Peltenburg, E. M. E. Verdegaal, A. Gorter, S. A. Bres, K. L. M. C. Franken, M. Hahne, J. P. Albar, C. J. M. Melief, et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors PNAS, September 13, 2001; (2001) 201398198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Medema, D. H. Schuurhuis, D. Rea, J. van Tongeren, J. de Jong, S. A. Bres, S. Laban, R. E.M. Toes, M. Toebes, T. N.M. Schumacher, et al. Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte-induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells J. Exp. Med., September 4, 2001; 194(5): 657 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Q. Zhao, M. K. Amir, W. R. Rice, and R. I. Enelow Type II Pneumocyte-CD8+ T-Cell Interactions . Relationship between Target Cell Cytotoxicity and Activation Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 362 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Bird, E. J. Blink, C. E. Hirst, M. S. Buzza, P. M. Steele, J. Sun, D. A. Jans, and P. I. Bird Nucleocytoplasmic Distribution of the Ovalbumin Serpin PI-9 Requires a Nonconventional Nuclear Import Pathway and the Export Factor Crm1 Mol. Cell. Biol., August 15, 2001; 21(16): 5396 - 5407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, J. M. Kelly, V. R. Sutton, J. E. Davis, K. A. Browne, T. J. Sayers, and J. A. Trapani Unlocking the secrets of cytotoxic granule proteins J. Leukoc. Biol., July 1, 2001; 70(1): 18 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Opferman, B. T. Ober, R. Narayanan, and P. G. Ashton-Rickardt Suicide induced by cytolytic activity controls the differentiation of memory CD8+ T lymphocytes Int. Immunol., April 1, 2001; 13(4): 411 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Suminami, S. Nagashima, A. Murakami, S. Nawata, T. Gondo, H. Hirakawa, F. Numa, G. A. Silverman, and H. Kato Suppression of a Squamous Cell Carcinoma (SCC)-related Serpin, SCC Antigen, Inhibits Tumor Growth with Increased Intratumor Infiltration of Natural Killer Cells Cancer Res., March 1, 2001; 61(5): 1776 - 1780. [Abstract] [Full Text]
|
|
|
|
|
|
B. A. Bladergroen, M. C. M. Strik, N. Bovenschen, O. van Berkum, G. L. Scheffer, C. J. L. M. Meijer, C. E. Hack, and J. A. Kummer The Granzyme B Inhibitor, Protease Inhibitor 9, Is Mainly Expressed by Dendritic Cells and at Immune-Privileged Sites J. Immunol., March 1, 2001; 166(5): 3218 - 3225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Young, G. K. Sukhova, D. Foster, W. Kisiel, P. Libby, and U. Schonbeck The Serpin Proteinase Inhibitor 9 Is an Endogenous Inhibitor of Interleukin 1{beta}-converting Enzyme (Caspase-1) Activity in Human Vascular Smooth Muscle Cells J. Exp. Med., May 1, 2000; 191(9): 1535 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kanamori, S. Krieg, C. Mao, V. A. Di Pippo, S. Wang, D. A. Zajchowski, and D. J. Shapiro Proteinase Inhibitor 9, an Inhibitor of Granzyme B-mediated Apoptosis, Is a Primary Estrogen-inducible Gene in Human Liver Cells J. Biol. Chem., February 25, 2000; 275(8): 5867 - 5873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Turner, M. C. Sancho, S. R. Thoennes, A. Caputo, R. C. Bleackley, and R. W. Moyer Myxoma Virus Serp2 Is a Weak Inhibitor of Granzyme B and Interleukin-1beta -Converting Enzyme In Vitro and Unlike CrmA Cannot Block Apoptosis in Cowpox Virus-Infected Cells J. Virol., August 1, 1999; 73(8): 6394 - 6404. [Abstract] [Full Text]
|
|
|
|
|
|
J. P. Galvin, L. H. A. Spaeny-Dekking, B. Wang, P. Seth, C. E. Hack, and C. J. Froelich Apoptosis Induced by Granzyme B-Glycosaminoglycan Complexes: Implications for Granule-Mediated Apoptosis In Vivo J. Immunol., May 1, 1999; 162(9): 5345 - 5350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Chuang and R. R. Schleef Identification of a Nuclear Targeting Domain in the Insertion between Helices C and D in Protease Inhibitor-10 J. Biol. Chem., April 16, 1999; 274(16): 11194 - 11198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. ten Berge, D. F. Dukers, J. J. Oudejans, K. Pulford, G. J. Ossenkoppele, D. de Jong, J. F.M.M. Misere, and C. J.L.M. Meijer Adverse Effects of Activated Cytotoxic T Lymphocytes on the Clinical Outcome of Nodal Anaplastic Large Cell Lymphoma Blood, April 15, 1999; 93(8): 2688 - 2696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Vermeer, F. A.M.J. Geelen, J. A. Kummer, C. J.L.M. Meijer, and R. Willemze Expression of Cytotoxic Proteins by Neoplastic T Cells in Mycosis Fungoides Increases with Progression from Plaque Stage to Tumor Stage Disease Am. J. Pathol., April 1, 1999; 154(4): 1203 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Scott, C. E. Hirst, J. Sun, C. H. Bird, S. P. Bottomley, and P. I. Bird The Intracellular Serpin Proteinase Inhibitor 6 Is Expressed in Monocytes and Granulocytes and Is a Potent Inhibitor of the Azurophilic Granule Protease, Cathepsin G Blood, March 15, 1999; 93(6): 2089 - 2097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Skold, B. Rosberg, U. Gullberg, and T. Olofsson A Secreted Proform of Neutrophil Proteinase 3 Regulates the Proliferation of Granulopoietic Progenitor Cells Blood, February 1, 1999; 93(3): 849 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Bird, V. R. Sutton, J. Sun, C. E. Hirst, A. Novak, S. Kumar, J. A. Trapani, and P. I. Bird Selective Regulation of Apoptosis: the Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated Apoptosis without Perturbing the Fas Cell Death Pathway Mol. Cell. Biol., November 1, 1998; 18(11): 6387 - 6398. [Abstract] [Full Text]
|
|
|
|
|
|
|
