Home LiteratureArticle Details
PMID: 11067865 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c.

The Journal of clinical investigation ·Vol. 106 ·No. 9 ·2000-11-00 ·Pages 1127-37

Guicciardi ME, Deussing J, Miyoshi H, Bronk SF, Svingen PA, Peters C, Kaufmann SH, Gores GJ

Abstract

TNF-alpha-induced apoptosis is thought to involve mediators from acidic vesicles. Cathepsin B (cat B), a lysosomal cysteine protease, has recently been implicated in apoptosis. To determine whether cat B contributes to TNF-alpha-induced apoptosis, we exposed mouse hepatocytes to the cytokine in vitro and in vivo. Isolated hepatocytes treated with TNF-alpha in the presence of the transcription inhibitor actinomycin D (AcD) accumulated cat B in their cytosol. Further experiments using cell-free systems indicated that caspase-8 caused release of active cat B from purified lysosomes and that cat B, in turn, increased cytosol-induced release of cytochrome c from mitochondria. Consistent with these observations, the ability of TNF-alpha/AcD to induce mitochondrial release of cytochrome c, caspase activation, and apoptosis of isolated hepatocytes was markedly diminished in cells from CatB(-/-) mice. Deletion of the CatB gene resulted in diminished liver injury and enhanced survival after treatment in vivo with TNF-alpha and an adenovirus construct expressing the IkappaB superrepressor. Collectively, these observations suggest that caspase-mediated release of cat B from lysosomes enhances mitochondrial release of cytochrome c and subsequent caspase activation in TNF-alpha-treated hepatocytes.

MeSH Terms
Animals Apoptosis/drug effects Biological Transport, Active/drug effects Caspases/metabolism Cathepsin B/deficiency,genetics,metabolism Cytochrome c Group/metabolism Cytosol/metabolism Dactinomycin/pharmacology Enzyme Activation/drug effects Hepatocytes/cytology,drug effects,metabolism Liver/drug effects,metabolism,pathology Mice Mice, Knockout Mitochondria/drug effects,metabolism Models, Biological Signal Transduction Tumor Necrosis Factor-alpha/metabolism,pharmacology
Chemicals
Cytochrome c Group Tumor Necrosis Factor-alpha Dactinomycin Caspases Cathepsin B
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Guicciardi M E
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
Deussing J
Miyoshi H
Bronk S F
Svingen P A
Peters C
Kaufmann S H
Gores G J
References (67)
67 references, click to expand
  1. Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins.
    Gastroenterology. 1997 Mar;112(3):923-34 PMID: 9041255
  2. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
    Science. 1997 Feb 21;275(5303):1129-32 PMID: 9027314
  3. Serial killers: ordering caspase activation events in apoptosis.
    Cell Death Differ. 1999 Nov;6(11):1067-74 PMID: 10578175
  4. Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.
    J Pharmacol Exp Ther. 1995 Feb;272(2):930-8 PMID: 7853211
  5. Role of an acidic compartment in tumor-necrosis-factor-alpha-induced production of ceramide, activation of caspase-3 and apoptosis.
    Eur J Biochem. 1998 Jan 15;251(1-2):295-303 PMID: 9492297
  6. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway.
    J Exp Med. 1997 Feb 3;185(3):481-90 PMID: 9053448
  7. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.
    Cell. 1995 May 19;81(4):495-504 PMID: 7758105
  8. Suppression of TNF-alpha-induced apoptosis by NF-kappaB.
    Science. 1996 Nov 1;274(5288):787-9 PMID: 8864120
  9. Death receptors in liver biology and pathobiology.
    Hepatology. 1999 Jan;29(1):1-4 PMID: 9862841
  10. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat.
    J Clin Invest. 1990 Jun;85(6):1936-43 PMID: 2161433
  11. Caspases induce cytochrome c release from mitochondria by activating cytosolic factors.
    J Biol Chem. 1999 Jun 18;274(25):17484-90 PMID: 10364179
  12. Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor.
    Cell. 1993 Apr 23;73(2):213-6 PMID: 8386591
  13. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration.
    J Clin Invest. 1998 Feb 15;101(4):802-11 PMID: 9466975
  14. Cell death induction by receptors of the TNF family: towards a molecular understanding.
    FEBS Lett. 1997 Jun 23;410(1):96-106 PMID: 9247131
  15. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner.
    J Cell Biol. 1999 Jan 25;144(2):281-92 PMID: 9922454
  16. Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation.
    Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4516-21 PMID: 9539769
  17. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis.
    Hepatology. 1989 Mar;9(3):349-51 PMID: 2920991
  18. The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition.
    J Biol Chem. 1996 Nov 22;271(47):29792-8 PMID: 8939917
  19. Two CD95 (APO-1/Fas) signaling pathways.
    EMBO J. 1998 Mar 16;17(6):1675-87 PMID: 9501089
  20. Additional members of the rat liver lamin polypeptide family. Structural and immunological characterization.
    J Biol Chem. 1989 Aug 15;264(23):13946-55 PMID: 2760052
  21. A simple procedure for the isolation of rat kidney lysosomes.
    Kidney Int. 1998 Jul;54(1):275-8 PMID: 9648089
  22. Tumor necrosis factor receptor-mediated signaling pathways.
    J Cell Biol. 1994 Jul;126(1):5-9 PMID: 8027185
  23. IAP family proteins--suppressors of apoptosis.
    Genes Dev. 1999 Feb 1;13(3):239-52 PMID: 9990849
  24. Hepatocytes sensitized to tumor necrosis factor-alpha cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways.
    J Biol Chem. 2000 Jan 7;275(1):705-12 PMID: 10617670
  25. Cystatin A expression reduces bile salt-induced apoptosis in a rat hepatoma cell line.
    Am J Physiol. 1998 Oct;275(4 Pt 1):G723-30 PMID: 9756503
  26. Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity.
    Biochem J. 1997 Jun 1;324 ( Pt 2):361-4 PMID: 9182691
  27. A simple procedure for the isolation of highly purified lysosomes from normal rat liver.
    J Biochem. 1984 Apr;95(4):1155-60 PMID: 6086593
  28. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
    Cell. 1998 Aug 21;94(4):491-501 PMID: 9727492
  29. Cathepsin B-mediated activation of the proinflammatory caspase-11.
    Biochem Biophys Res Commun. 1998 Oct 9;251(1):379-87 PMID: 9790964
  30. Caspase-independent cell killing by Fas-associated protein with death domain.
    J Cell Biol. 1998 Nov 30;143(5):1353-60 PMID: 9832562
  31. Characterization of caspase processing and activation in HL-60 cell cytosol under cell-free conditions. Nucleotide requirement and inhibitor profile.
    J Biol Chem. 1999 Aug 6;274(32):22635-45 PMID: 10428844
  32. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.
    Cell. 1996 Jan 26;84(2):299-308 PMID: 8565075
  33. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release.
    Mol Cell Biol. 1998 Nov;18(11):6353-64 PMID: 9774651
  34. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex.
    Cell. 1996 Jun 14;85(6):817-27 PMID: 8681377
  35. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas.
    J Clin Invest. 1999 Jan;103(1):137-45 PMID: 9884343
  36. RAIDD is a new 'death' adaptor molecule.
    Nature. 1997 Jan 2;385(6611):86-9 PMID: 8985253
  37. A comparison of cathepsin B processing and distribution during neuronal death in rats following global ischemia or decapitation necrosis.
    Brain Res. 1997 Mar 21;751(2):206-16 PMID: 9099807
  38. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.
    Cell. 1993 May 7;73(3):431-45 PMID: 8387891
  39. Tumor necrosis factor receptor and Fas signaling mechanisms.
    Annu Rev Immunol. 1999;17:331-67 PMID: 10358762
  40. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.
    Cell. 1996 Jun 14;85(6):803-15 PMID: 8681376
  41. Proteolytic processing and glycosylation of cathepsin B. The role of the primary structure of the latent precursor and of the carbohydrate moiety for cell-type-specific molecular forms of the enzyme.
    Biochem J. 1992 Mar 1;282 ( Pt 2):577-82 PMID: 1312333
  42. Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12507-12 PMID: 8901612
  43. Activation of multiple interleukin-1beta converting enzyme homologues in cytosol and nuclei of HL-60 cells during etoposide-induced apoptosis.
    J Biol Chem. 1997 Mar 14;272(11):7421-30 PMID: 9054443
  44. Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis.
    J Exp Med. 1994 Mar 1;179(3):841-8 PMID: 7509363
  45. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis.
    J Biol Chem. 1996 Mar 1;271(9):4961-5 PMID: 8617770
  46. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha.
    EMBO J. 1996 Aug 1;15(15):3861-70 PMID: 8670891
  47. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death.
    J Biol Chem. 1999 Jan 8;274(2):1156-63 PMID: 9873064
  48. Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity.
    FEBS Lett. 1998 Nov 6;438(3):150-8 PMID: 9827536
  49. 1-Methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis.
    Mol Pharmacol. 1998 Nov;54(5):789-801 PMID: 9804614
  50. Differential modulation of apoptosis sensitivity in CD95 type I and type II cells.
    J Biol Chem. 1999 Aug 6;274(32):22532-8 PMID: 10428830
  51. Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation.
    J Biol Chem. 1999 Jan 8;274(2):787-94 PMID: 9873017
  52. Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress.
    Free Radic Biol Med. 1999 Dec;27(11-12):1228-37 PMID: 10641715
  53. Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes.
    Gastroenterology. 1997 Nov;113(5):1714-26 PMID: 9352877
  54. Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c.
    J Biol Chem. 1998 Jun 26;273(26):16589-94 PMID: 9632731
  55. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.
    Nat Med. 1996 Jan;2(1):80-6 PMID: 8564847
  56. Activation of procathepsin B in human hepatoma cells: the conversion into the mature enzyme relies on the action of cathepsin B itself.
    Biochem J. 1993 Jul 15;293 ( Pt 2):437-42 PMID: 8393661
  57. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis.
    J Neurosci. 1995 Feb;15(2):1001-11 PMID: 7869078
  58. Rat procathepsin B. Proteolytic processing to the mature form in vitro.
    J Biol Chem. 1992 Aug 5;267(22):15993-9 PMID: 1639824
  59. Analysis of the internal nuclear matrix. Oligomers of a 38 kD nucleolar polypeptide stabilized by disulfide bonds.
    Exp Cell Res. 1986 May;164(1):139-53 PMID: 3514251
  60. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
    Cell. 1998 Aug 21;94(4):481-90 PMID: 9727491
  61. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes.
    Nature. 1993 Aug 26;364(6440):798-802 PMID: 8395024
  62. Calpain and cell death.
    Cell Death Differ. 1996 Jul;3(3):275-83 PMID: 17180096
  63. Functions of ceramide in coordinating cellular responses to stress.
    Science. 1996 Dec 13;274(5294):1855-9 PMID: 8943189
  64. Tumor necrosis factor receptors--structure and function.
    Immunol Res. 1992;11(2):81-90 PMID: 1331273
  65. NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis.
    Am J Physiol. 1998 Oct;275(4 Pt 1):C1058-66 PMID: 9755059
  66. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.
    Cell. 1999 Jul 9;98(1):47-58 PMID: 10412980
  67. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
    Science. 1998 Sep 11;281(5383):1680-3 PMID: 9733516
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI9914
Published
2000-11-00
Pages
1127-37
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC301415
Subset
IM
Grants
NIDDK NIH HHS · DK 41876 · United States
NCI NIH HHS · CA69008 · United States
NIDDK NIH HHS · R01 DK041876 · United States
NIDDK NIH HHS · R37 DK041876 · United States
NCI NIH HHS · R01 CA069008 · United States
Corrections
CommentIn
PMID: 11134173
External Links
PubMed source DOI: 10.1172/JCI9914 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2