Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents
Open accessAbstract
Necrotic cell death triggers a range of biological responses including a strong adaptive immune response, yet we know little about the cellular pathways that control necrotic cell death. Inhibitor studies suggest that proteases, and in particular cathepsins, drive necrotic cell death. The cathepsin B-selective inhibitor CA-074-Me blocks all forms of programmed necrosis by an unknown mechanism. We found that cathepsin B deficiency does not prevent induction of pyroptosis and lysosome-mediated necrosis suggesting that CA-074-Me blocks necrotic cell death by targeting cathepsins other than cathepsin B. A single cathepsin, cathepsin C, drives necrotic cell death mediated by the lysosome-destabilizing agent Leu-Leu-OMe (LLOMe). Here we present evidence that cathepsin C-deficiency and CA-074-Me block LLOMe killing in a distinct and cell type-specific fashion. Cathepsin C-deficiency and CA-074-Me block LLOMe killing of all myeloid cells, except for neutrophils. Cathepsin C-deficiency, but not CA-074-Me, blocks LLOMe killing of neutrophils suggesting that CA-074-Me does not target cathepsin C directly, consistent with inhibitor studies using recombinant cathepsin C. Unlike other cathepsins, cathepsin C lacks endoproteolytic activity, and requires activation by other lysosomal proteases, such as cathepsin D. Consistent with this theory, we found that lysosomotropic agents and cathepsin D downregulation by siRNA block LLOMe-mediated necrosis. Our findings indicate that a proteolytic cascade, involving cathepsins C and D, controls LLOMe-mediated necrosis. In contrast, cathepsins C and D were not required for pyroptotic cell death suggesting that distinct cathepsins control pyroptosis and lysosome-mediated necrosis.
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Lysosome-dependent cell death does not necessarily involve MOMP and caspases, nor necessarily manifest with an apoptotic morphotype.
“Of note, lysosome-dependent cell death does not necessarily involve MOMP and caspases, and does not necessarily manifest with an apoptotic morphotype [782].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [782]
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Cites
Martinon, F., Burns, K., & Tschopp, J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00599-3 · Cited by 6,066 · see citing works
Gout-associated uric acid crystals activate the NALP3 inflammasome
Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., & Tschopp, J. (2006) · Nature · doi:10.1038/nature04516 · Cited by 5,326 · see citing works
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221 · see citing works
Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009
Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., El-Deiry, W. S., Golstein, P., Green, D. R., et al. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.150 · Cited by 3,399 · see citing works
Pyroptosis: host cell death and inflammation
Bergsbaken, T., Fink, S. L., & Cookson, B. T. (2009) · Nature Reviews Microbiology · doi:10.1038/nrmicro2070 · Cited by 3,185 · see citing works
Cryopyrin activates the inflammasome in response to toxins and ATP
Mariathasan, S., Weiss, D. S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W. P., Weinrauch, Y., Monack, D. M., & Dixit, V. M. (2006) · Nature · doi:10.1038/nature04515 · Cited by 3,080 · see citing works
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A., & Yuan, J. (2005) · Nature Chemical Biology · doi:10.1038/nchembio711 · Cited by 3,068 · see citing works
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., & Latz, E. (2008) · Nature Immunology · doi:10.1038/ni.1631 · Cited by 3,065 · see citing works
Molecular mechanisms of necroptosis: an ordered cellular explosion
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., & Kroemer, G. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2970 · Cited by 2,382 · see citing works
Franchi, L., Eigenbrod, T., Muñoz-Planillo, R., & Nuñez, G. (2009) · Nature Immunology · doi:10.1038/ni.1703 · Cited by 1,834 · see citing works
How dying cells alert the immune system to danger
Kono, H., & Rock, K. L. (2008) · Nature Reviews Immunology · doi:10.1038/nri2215 · Cited by 1,737 · see citing works
Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death
Casares, N., Pequignot, M. O., Tesniere, A., Ghiringhelli, F., Roux, S., Chaput, N., Schmitt, E., Hamai, A., Hervas-Stubbs, S., Obeid, M., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050915 · Cited by 1,512 · see citing works
Negative regulation of Toll-like receptor-mediated immune responses
Liew, F. Y., Xu, D., Brint, E. K., & O'Neill, L. A. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1630 · Cited by 1,509 · see citing works
Death by design: apoptosis, necrosis and autophagy
Edinger, A. L., & Thompson, C. B. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2004.09.011 · Cited by 1,364 · see citing works
Basu, S., Binder, R. J., Suto, R., Anderson, K. M., & Srivastava, P. K. (2000) · International Immunology · doi:10.1093/intimm/12.11.1539 · Cited by 1,305 · see citing works
Fink, S. L., & Cookson, B. T. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00751.x · Cited by 1,114 · see citing works
Kool, M., Soullié, T., van Nimwegen, M., Willart, M. A. M., Muskens, F., Jung, S., Hoogsteden, H. C., Hammad, H., & Lambrecht, B. N. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071087 · Cited by 985 · see citing works
Active Caspase-1 Is a Regulator of Unconventional Protein Secretion
Keller, M., Rüegg, A., Werner, S., & Beer, H. (2008) · Cell · doi:10.1016/j.cell.2007.12.040 · Cited by 851 · see citing works
Classification of cell death: recommendations of the Nomenclature Committee on Cell Death
Kroemer, G., El-Deiry, W. S., Golstein, P., Peter, M. E., Vaux, D., Vandenabeele, P., Zhivotovsky, B., Blagosklonny, M. V., Malorni, W., Knight, R. A., et al. (2005) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401724 · Cited by 843 · see citing works
Necroptosis as an alternative form of programmed cell death
Christofferson, D. E., & Yuan, J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.12.003 · Cited by 771 · see citing works
TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity
Creagh, E. M., & O’Neill, L. A. J. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.06.003 · Cited by 762 · see citing works
Lysosomal cysteine proteases: facts and opportunities
Türk, V., Turk, B., & Turk, D. (2001) · The EMBO Journal · doi:10.1093/emboj/20.17.4629 · Cited by 758 · see citing works
Festjens, N., Vanden Berghe, T., & Vandenabeele, P. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.06.014 · Cited by 710 · see citing works
The inflammasome: a danger sensing complex triggering innate immunity
Pétrilli, V., Dostert, C., Muruve, D. A., & Tschopp, J. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.09.002 · Cited by 700 · see citing works
Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes
Galluzzi, L., Aaronson, S. A., Abrams, J., Alnemri, E. S., Andrews, D. W., Baehrecke, E. H., Bazan, N. G., Blagosklonny, M. V., Blomgren, K., Borner, C., et al. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.44 · Cited by 698 · see citing works
Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
Iyer, S. S., Pulskens, W. P., Sadler, J. J., Butter, L. M., Teske, G. J., Ulland, T. K., Eisenbarth, S. C., Florquin, S., Flavell, R. A., Leemans, J. C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908698106 · Cited by 691 · see citing works
Salmonella induces macrophage death by caspase‐1‐dependent necrosis
Brennan, M. A., & Cookson, B. T. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.02103.x · Cited by 674 · see citing works
Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features
Berghe, T. V., Vanlangenakker, N., Parthoens, E., Deckers, W., Devos, M., Festjens, N., Guerin, C. J., Brunk, U. T., Declercq, W., & Vandenabeele, P. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.184 · Cited by 639 · see citing works
HMGB1 is an endogenous immune adjuvant released by necrotic cells
Rovere, P. Q., Capobianco, A., Scaffidi, P., Valentinis, B., Catalanotti, F., Giazzon, M., Dumitriu, I. E., Müller, S., Iannacone, M., Traversari, C., et al. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400205 · Cited by 591 · see citing works
DNA released from dying host cells mediates aluminum adjuvant activity
Marichal, T., Ohata, K., Bedoret, D., Mesnil, C., Sabatel, C. M., Kobiyama, K., Lekeux, P. M., Coban, C., Akira, S., Ishii, K. J., et al. (2011) · Nature Medicine · doi:10.1038/nm.2403 · Cited by 538 · see citing works
Bidère, N., Lorenzo, H. K., Carmona, S., Laforge, M., Harper, F., Dumont, C., & Senik, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301911200 · Cited by 435 · see citing works
Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity
Aymeric, L., Apétoh, L., Ghiringhelli, F., Tesnière, A., Martins, I., Kroemer, G., Smyth, M. J., & Zitvogel, L. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3566 · Cited by 380 · see citing works
NLRs at the intersection of cell death and immunity
Ting, J. P.-Y., Willingham, S. B., & Bergstralh, D. T. (2008) · Nature Reviews Immunology · doi:10.1038/nri2296 · Cited by 371 · cited 1× · see citing works
“For example, necrotic cell death has been linked to microbial pathogenesis, ischemic stroke, and induction of adaptive immune responses.(20,27,30,33,46,52) While most attention has focused on apoptotic cell death, recent evidence suggests that necrotic, like apoptotic cell death is a highly regulated process.”
BackgroundThiele, D. L., & Lipsky, P. E. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.1.83 · Cited by 264 · see citing works
Cathepsin D is membrane-associated in macrophage endosomes.
Diment, S., Leech, M. S., & Stahl, P. D. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68729-0 · Cited by 260 · see citing works
Apoptosis without caspases: an inefficient molecular guillotine?
Borner, C., & Monney, L. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400525 · Cited by 244 · see citing works
Apoptotic Pathways: Involvement of Lysosomal Proteases
Turk, B., Stoka, V., Pungerčar, J. R., Cirman, T., Droga-Mazovec, G., Oreic, K., & Türk, V. (2002) · Biological Chemistry · doi:10.1515/bc.2002.112 · Cited by 206 · see citing works
Guicciardi, M. E., Miyoshi, H., Bronk, S. F., & Gores, G. J. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63056-8 · Cited by 204 · see citing works
CA074 methyl ester: A proinhibitor for intracellular cathepsin B
Buttle, D. J., Murata, M., Knight, C. G., & Barrett, A. J. (1992) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(92)90290-d · Cited by 201 · see citing works
Oberle, C., Huai, J., Reinheckel, T., Tacke, M., Rassner, M., Ekert, P. G., Buellesbach, J., & Borner, C. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.214 · Cited by 193 · see citing works
Hentze, H., Lin, X. Y., Choi, M. S. K., & Porter, A. G. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401264 · Cited by 187 · see citing works
Dahl, S. W., Halkier, T., Lauritzen, C., et al. (2001) · Biochemistry · doi:10.1021/bi001693z · Cited by 164 · see citing works
Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death
Lima, H., Jacobson, L. S., Goldberg, M. F., Chandran, K., Diaz‐Griffero, F., Lisanti, M. P., & Brojatsch, J. (2013) · Cell Cycle · doi:10.4161/cc.24903 · Cited by 164 · see citing works
Self-citationCutting Edge: Necrosis Activates the NLRP3 Inflammasome
Li, H., Ambade, A., & Re, F. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901080 · Cited by 127 · see citing works
Fujisawa, A., Kambe, N., Saito, M. K., Nishikomori, R., Tanizaki, H., Kanazawa, N., Adachi, S., Heike, T., Sagara, J., Suda, T., et al. (2006) · Blood · doi:10.1182/blood-2006-07-033597 · Cited by 101 · see citing works
CA-074Me Protection against Anthrax Lethal Toxin
Newman, Z. L., Leppla, S. H., & Moayeri, M. (2009) · Infection and Immunity · doi:10.1128/iai.00730-09 · Cited by 90 · see citing works
Muehlbauer, S. M., Evering, T. H., Bonuccelli, G., Squires, R. C., Ashton, A. W., Porcelli, S. A., Lisanti, M. P., & Brojatsch, J. (2007) · Cell Cycle · doi:10.4161/cc.6.6.3991 · Cited by 83 · see citing works
Self-citationProteasomes Control Caspase-1 Activation in Anthrax Lethal Toxin-mediated Cell Killing
Squires, R. C., Muehlbauer, S. M., & Brojatsch, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705687200 · Cited by 79 · see citing works
Self-citationKimmins, S., & MacRae, T. H. (2000) · Cell Stress and Chaperones · doi:10.1379/1466-1268(2000)005 · Cited by 75 · see citing works
Jacobson, L. S., Lima, H., Goldberg, M. F., Gocheva, V., Tsiperson, V., Sutterwala, F. S., Joyce, J. A., Gapp, B. V., Blomen, V. A., Chandran, K., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.400655 · Cited by 74 · see citing works
Self-citationAverette, K. M., Pratt, M. R., Yang, Y., Bassilian, S., Whitelegge, J. P., Loo, J. A., Muir, T. W., & Bradley, K. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007913 · Cited by 66 · see citing works
Thiele, D. L., & Lipsky, P. E. (1990) · The Journal of Experimental Medicine · doi:10.1084/jem.172.1.183 · Cited by 66 · see citing works
Effects of cysteine protease inhibitors on rabbit cathepsin D maturation
Samarel, A. M., Ferguson, A. G., Decker, R. S., & Lesch, M. (1989) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1989.257.6.c1069 · Cited by 62 · see citing works
Complete lysosomal disruption: A route to necrosis, not to the inflammasome
Guicciardi, M. E., & Gores, G. J. (2013) · Cell Cycle · doi:10.4161/cc.25317 · Cited by 24 · see citing works
Muehlbauer, S. M., Lima, H., Goldman, D. L., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090828 · Cited by 17 · see citing works
Self-citationReinheckel, T. (2013) · Cell Cycle · doi:10.4161/cc.25316 · Cited by 15 · see citing works
Molecular determinants for a cardiovascular collapse in anthrax
Goldman, D. L. (2014) · Frontiers in Bioscience-Elite · doi:10.2741/e697 · Cited by 11 · see citing works
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41
Carey, K. L., Paulus, G. L. C., Wang, L., Balce, D. R., Luo, J. W., Bergman, P., Ferder, I. C., Kong, L., Renaud, N., Singh, S., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108371 · Cited by 55 · see citing works
- Authors
- Brojatsch, J., Lima, H., Palliser, D., Jacobson, L. S., Muehlbauer, S. M., Furtado, R., Goldman, D. L., Lisanti, M. P., & Chandran, K.
- Affiliations
- Albert Einstein College of Medicine (US)
- Beth Israel Deaconess Medical Center (US)
- University of Manchester (GB)
- Corresponding author
- Lisanti, Michael P
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2015-04-01
- Volume
- 14
- Issue
- 7
- Pages
- 964-972
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC4614982
- OpenAlex
- W2027390173
- Cited by
- 50
- References
- 57
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 2 · 2016: 2
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- National Institutes of Health (1r56ai092497-01a1)
- National Institute of Allergy and Infectious Diseases (1R56AI092497-01A1, R01AI088027, R01AI099567, U54AI057158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- necrosis, cathepsin C, cathepsin D, pyroptosis, cathepsin B, proteolytic cascade, neutrophils, myeloid cells, lysosomal proteases, cell death regulation
- MeSH terms
- Animals, Cathepsin B, Cathepsin D, Dipeptides, Lysosomes, Mice, Inbred BALB C, Mice, Inbred C57BL, Necrosis, Apoptosis, Cathepsin C
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