NDLI: A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic Lymphocytes

Content Provider	Journal of Biological Chemistry (JBC)
Author	Sun, Jiuru Bird, Catherina H. Sutton, Vivien McDonald, Lisa Coughlin, Paul B. Jong, Tanya A. De Trapani, Joseph A. Bird, Phillip I.
Abstract	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′(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 s−1, 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.
Related Links	http://www.jbc.org/content/271/44/27802.abstract
Ending Page	27809
Starting Page	27802
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	44
Volume Number	271
DOI	10.1074/jbc.271.44.27802
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1996-11-01
Access Restriction	Open
Subject Keyword	Nucleic Acids, Protein Synthesis, and Molecular Genetics
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Residual Cytotoxicity and Granzyme K Expression in Granzyme A-deficient Cytotoxic Lymphocytes

Cytotoxic T Lymphocyte-assisted Suicide CASPASE 3 ACTIVATION IS PRIMARILY THE RESULT OF THE DIRECT ACTION OF GRANZYME B

Granzyme B Is Inhibited by the Cowpox Virus Serpin Cytokine Response Modifier A

A New Family of 10 Murine Ovalbumin Serpins Includes Two Homologs of Proteinase Inhibitor 8 and Two Homologs of the Granzyme B Inhibitor (Proteinase Inhibitor 9)

DNA-dependent Protein Kinase Is a Target for a CPP32-like Apoptotic Protease

Transcription of the blk Gene in Human B Lymphocytes Is Controlled by Two Promoters

In Vivo Regulation of Murine Granzyme B Gene Transcription in Activated Primary T Cells

A Consensus Insulin Response Element Is Activated by an ETS-related Transcription Factor

Mutational Analysis of the Murine Granzyme B Gene Promoter in Primary T Cells and a T Cell Clone

A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic Lymphocytes

Similar Documents

Residual Cytotoxicity and Granzyme K Expression in Granzyme A-deficient Cytotoxic Lymphocytes

Cytotoxic T Lymphocyte-assisted Suicide CASPASE 3 ACTIVATION IS PRIMARILY THE RESULT OF THE DIRECT ACTION OF GRANZYME B

Granzyme B Is Inhibited by the Cowpox Virus Serpin Cytokine Response Modifier A

A New Family of 10 Murine Ovalbumin Serpins Includes Two Homologs of Proteinase Inhibitor 8 and Two Homologs of the Granzyme B Inhibitor (Proteinase Inhibitor 9)

DNA-dependent Protein Kinase Is a Target for a CPP32-like Apoptotic Protease

Transcription of the blk Gene in Human B Lymphocytes Is Controlled by Two Promoters

In Vivo Regulation of Murine Granzyme B Gene Transcription in Activated Primary T Cells

A Consensus Insulin Response Element Is Activated by an ETS-related Transcription Factor

Mutational Analysis of the Murine Granzyme B Gene Promoter in Primary T Cells and a T Cell Clone

A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic Lymphocytes