Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation

Shi, Lei; Wu, Lianfeng; Wang, S; Fan, Z

doi:10.1038/cdd.2009.101

Cited by 22 publications

(23 citation statements)

References 43 publications

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“…Our laboratory compared several delivery agents to load granzymes (Gzms) into target cells, including perforin, SLO, and a cationic lipid protein transfection agent, Pro-Ject (7,21). We found SLO was efficiently delivered Gzms into target cells to induce cytolysis with similar kinetics of perforin delivery, which is in agreement with a previous report (6).…”

Section: Gzmh Inhibits Hbv Replicationsupporting

confidence: 79%

“…RC, relaxed circular; SS, single-stranded viral DNAs. mGzmH) were prepared as described previously (21). Mouse NK cells were isolated from splenocytes through a positive NK isolation kit (Miltenyi Biotec) and infected with Ad-GzmH or Ad-mGzmH at 300 PFU/cell for 6 h. pAAV-HBV 1.2 plasmid was a kind gift from Dr. Ding-Shinn Chen (National Taiwan University and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan).…”

Section: Southern Blotmentioning

confidence: 99%

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Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

Tang

Wang

et al. 2012

The Journal of Immunology

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The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met79 by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.

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Section: Gzmh Inhibits Hbv Replicationsupporting

confidence: 79%

Section: Southern Blotmentioning

confidence: 99%

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

Tang

Wang

et al. 2012

The Journal of Immunology

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“…60 Treatment of YAC-1 target cells with GrF and adenovirus, perforin, or streptolysin O resulted in a form of cell death that was characterized by phosphatidylserine exposure, plasma membrane permeability, mitochondrial swelling and damage, and partial chromatin condensation. Cell death was unimpeded in the presence of caspase inhibitors, and the cells did not show signs of caspase activation, despite the release of cytochrome C from the mitochondria.…”

Section: Mechanisms Of Cytotoxicity and Physiological Roles Of Grsmentioning

confidence: 99%

A quarter century of granzymes

2011

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“…GzmH was loaded into Jurkat cells with 80 ng/ml streptolysin O (SLO; Sigma-Aldrich), as described (30). Briefly, SLO was preactivated by 10 mM DTT for 10 min.…”

Section: Loading Gzmh With Streptolysin Omentioning

confidence: 99%

Structural Insights into the Substrate Specificity of Human Granzyme H: The Functional Roles of a Novel RKR Motif

Wang

Zhang

et al. 2012

The Journal of Immunology

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Human granzyme H (GzmH) is constitutively expressed in human NK cells that have important roles in innate immune responses against tumors and viruses. GzmH is a chymotrypsin-like serine protease. Its substrate preference and its mechanism of substrate recognition are poorly understood. To provide structural insights into the substrate recognition mechanisms for GzmH, we solved the crystal structures of a D102N-GzmH mutant alone and in complex with a decapeptide substrate and an inhibitor to 2.2 Å, 2.4 Å, and 2.7 Å, respectively. The Thr189, Gly216, and Gly226 specificity triad in the S1 pocket of GzmH defines its preference for bulky, aromatic residues (Tyr and Phe) at the P1 position. Notably, we discovered that an unusual RKR motif (Arg39-Lys40-Arg41), conserved only in GzmH, helps define the S3′ and S4′ binding regions, indicating the preference for acidic residues at the P3′ and P4′ sites. Disruption of the RKR motif or the acidic P3′ and P4′ residues in the substrate abolished the proteolytic activity of GzmH. We designed a tetrapeptide chloromethylketone inhibitor, Ac-PTSY-chloromethylketone, which can selectively and efficiently block the enzymatic and cytotoxic activity of GzmH, providing a useful tool for further studies on the function of GzmH.

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Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation

Cited by 22 publications

References 43 publications

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

A quarter century of granzymes

Structural Insights into the Substrate Specificity of Human Granzyme H: The Functional Roles of a Novel RKR Motif

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