Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B

Lianfa Shi, Gao Chen, Glen Macdonald, Louise Bergeron, Honglin Li, Masayuki Miura, Rocco J. Rotello, Douglas K. Miller, Ping Li, Tara Seshadri, Junying Yuan, Arnold H. Greenberg

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B- based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro.interleukin 1β converting enzyme (ICE) and pro- CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or lch-IS that exhibit resistance to granzyme B, CPP32 is processed to pl7 and poly(ADP- ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34(cdc2) kinase, which is required for granzyme B- induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.

Original languageEnglish (US)
Pages (from-to)11002-11007
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number20
DOIs
StatePublished - Oct 1 1996
Externally publishedYes

Fingerprint

Granzymes
Caspase 1
Apoptosis
Peptide Hydrolases
Cytotoxic T-Lymphocytes
HeLa Cells
B-Lymphocytes
Poly(ADP-ribose) Polymerases
Thymocytes

Keywords

  • CPP32
  • Fas
  • Ich-IS
  • poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • General

Cite this

Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. / Shi, Lianfa; Chen, Gao; Macdonald, Glen; Bergeron, Louise; Li, Honglin; Miura, Masayuki; Rotello, Rocco J.; Miller, Douglas K.; Li, Ping; Seshadri, Tara; Yuan, Junying; Greenberg, Arnold H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 20, 01.10.1996, p. 11002-11007.

Research output: Contribution to journalArticle

Shi, L, Chen, G, Macdonald, G, Bergeron, L, Li, H, Miura, M, Rotello, RJ, Miller, DK, Li, P, Seshadri, T, Yuan, J & Greenberg, AH 1996, 'Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B', Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 20, pp. 11002-11007. https://doi.org/10.1073/pnas.93.20.11002
Shi, Lianfa ; Chen, Gao ; Macdonald, Glen ; Bergeron, Louise ; Li, Honglin ; Miura, Masayuki ; Rotello, Rocco J. ; Miller, Douglas K. ; Li, Ping ; Seshadri, Tara ; Yuan, Junying ; Greenberg, Arnold H. / Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 20. pp. 11002-11007.
@article{f48857659036411dbd669e81b8de4ed1,
title = "Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B",
abstract = "Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B- based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro.interleukin 1β converting enzyme (ICE) and pro- CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or lch-IS that exhibit resistance to granzyme B, CPP32 is processed to pl7 and poly(ADP- ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34(cdc2) kinase, which is required for granzyme B- induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.",
keywords = "CPP32, Fas, Ich-IS, poly(ADP-ribose) polymerase",
author = "Lianfa Shi and Gao Chen and Glen Macdonald and Louise Bergeron and Honglin Li and Masayuki Miura and Rotello, {Rocco J.} and Miller, {Douglas K.} and Ping Li and Tara Seshadri and Junying Yuan and Greenberg, {Arnold H.}",
year = "1996",
month = "10",
day = "1",
doi = "10.1073/pnas.93.20.11002",
language = "English (US)",
volume = "93",
pages = "11002--11007",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "20",

}

TY - JOUR

T1 - Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B

AU - Shi, Lianfa

AU - Chen, Gao

AU - Macdonald, Glen

AU - Bergeron, Louise

AU - Li, Honglin

AU - Miura, Masayuki

AU - Rotello, Rocco J.

AU - Miller, Douglas K.

AU - Li, Ping

AU - Seshadri, Tara

AU - Yuan, Junying

AU - Greenberg, Arnold H.

PY - 1996/10/1

Y1 - 1996/10/1

N2 - Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B- based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro.interleukin 1β converting enzyme (ICE) and pro- CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or lch-IS that exhibit resistance to granzyme B, CPP32 is processed to pl7 and poly(ADP- ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34(cdc2) kinase, which is required for granzyme B- induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.

AB - Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B- based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro.interleukin 1β converting enzyme (ICE) and pro- CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or lch-IS that exhibit resistance to granzyme B, CPP32 is processed to pl7 and poly(ADP- ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34(cdc2) kinase, which is required for granzyme B- induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.

KW - CPP32

KW - Fas

KW - Ich-IS

KW - poly(ADP-ribose) polymerase

UR - http://www.scopus.com/inward/record.url?scp=16044372676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16044372676&partnerID=8YFLogxK

U2 - 10.1073/pnas.93.20.11002

DO - 10.1073/pnas.93.20.11002

M3 - Article

VL - 93

SP - 11002

EP - 11007

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 20

ER -