Online citations, reference lists, and bibliographies.
← Back to Search

The Serine Protease Inhibitor TLCK Attenuates Intrinsic Death Pathways In Neurons Upstream Of Mitochondrial Demise

C. Reuther, G. Ganjam, A. Dolga, C. Culmsee
Published 2014 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces oxytosis, a form of caspase-independent cell death that involves activation of the pro-apoptotic protein BH3 interacting-domain death agonist (Bid), leading to mitochondrial demise and ensuing cell death. In this model system, the trypsin-like serine protease inhibitor Nα-tosyl-l-lysine chloromethyl ketone hydrochloride (TLCK) inhibited mitochondrial damage and cell death. Mitochondrial morphology alterations, the impairment of the mitochondrial membrane potential and ATP depletion were prevented and, moreover, lipid peroxidation induced by glutamate was completely abolished. Strikingly, truncated Bid-induced cell death was not affected by TLCK, suggesting a detrimental activity of serine proteases upstream of Bid activation and mitochondrial demise. In summary, this study demonstrates the protective effect of serine protease inhibition by TLCK against oxytosis-induced mitochondrial damage and cell death. These findings indicate that TLCK-sensitive serine proteases play a crucial role in cell death mechanisms upstream of mitochondrial demise and thus, may serve as therapeutic targets in diseases, where oxidative stress and intrinsic pathways of PCD mediate neuronal cell death.
This paper references
10.1038/ncb1101-e255
Organelle-specific initiation of cell death pathways
K. Ferri (2001)
10.1016/j.jjcc.2010.10.001
Granzyme B as a novel factor involved in cardiovascular diseases.
Y. Saito (2011)
10.1042/BST0350559
The emerging role of serine proteases in apoptosis.
K. Moffitt (2007)
10.1038/cdd.2010.92
Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons
S. Tobaben (2011)
10.1074/JBC.M410985200
A Central Role for Bid in Granzyme B-induced Apoptosis*
N. Waterhouse (2005)
10.1042/BJ3240361
Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity.
Q. Zhou (1997)
10.2174/156720506778249461
Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders.
C. Culmsee (2006)
10.1042/0264-6021:3470669
Serine protease inhibitors suppress cytochrome c-mediatedcaspase-9 activation and apoptosis during hypoxia-reoxygenation.
Z. Dong (2000)
10.1016/S0165-0173(97)00015-5
The role of thrombin-like (serine) proteases in the development, plasticity and pathology of the nervous system
V. Turgeon (1997)
10.1006/BBRC.1994.2161
Interleukin-1β Induced Activation of NF-κB in Insulin-Producing RINm5F Cells Is Prevented by the Protease Inhibitor Nα-p-Tosyl-L-Lysine Chloromethylketone
J. Saldeen (1994)
10.1016/0014-5793(85)81315-6
N‐α‐Tosyl‐L‐lysine chloromethyl ketone and N‐α‐tosyl‐L‐phenylalanine chloromethyl ketone inhibit protein kinase C
D. Solomon (1985)
10.1073/PNAS.76.7.3073
Affinity labeling of the catalytic subunit of cyclic AMP-dependent protein kinase by N alpha-tosyl-L-lysine chloromethyl ketone.
A. Kupfer (1979)
10.1016/J.FREERADBIOMED.2006.12.030
Cathepsin D-Bax death pathway in oxidative stressed neuroblastoma cells.
R. Castino (2007)
Chloromethyl ketones block induction of nitric oxide synthase in murine macrophages by preventing activation of nuclear factor-kappa B.
H. Kim (1995)
10.1074/jbc.M709789200
Chymotrypsin B Cached in Rat Liver Lysosomes and Involved in Apoptotic Regulation through a Mitochondrial Pathway*
Q. Miao (2008)
10.1016/J.TCB.2004.03.002
Death without caspases, caspases without death.
M. C. Abraham (2004)
10.1242/jcs.070490
New insights into the role of mitochondria in aging: mitochondrial dynamics and more
A. Y. Seo (2010)
10.1002/jnr.10008
Involvement of TLCK‐sensitive serine protease in colchicine‐induced cell death of sympathetic neurons in culture
C. Mitsui (2001)
Involvement of both caspaselike proteases and serine proteases in apoptotic cell death
N Komatsu (1998)
10.1073/PNAS.90.17.7951
Apoptosis is induced by beta-amyloid in cultured central nervous system neurons.
D. Loo (1993)
10.3410/f.3063959.2745058
Faculty Opinions recommendation of Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis.
A. Means (2010)
10.1016/j.bbi.2009.11.015
Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death
J. Grohm (2010)
10.1007/s10495-007-0756-2
Mitochondria, oxidative stress and cell death
M. Ott (2007)
10.1074/JBC.M308347200
Selective Disruption of Lysosomes in HeLa Cells Triggers Apoptosis Mediated by Cleavage of Bid by Multiple Papain-like Lysosomal Cathepsins*
T. Cirman (2004)
10.1101/GAD.13.24.3179
Caspase-9 and APAF-1 form an active holoenzyme.
J. Rodriguez (1999)
Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases.
B. Gong (1999)
10.1074/jbc.274.17.11549
An APAF-1·Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9*
H. Zou (1999)
10.1007/s00018-010-0356-0
Lysosomal chymotrypsin B potentiates apoptosis via cleavage of Bid
Kai Zhao (2010)
10.1016/j.jneumeth.2011.09.012
Impedance measurement for real time detection of neuronal cell death
S. Diemert (2012)
10.1038/sj.embor.7400892
Ischaemic brain damage after stroke: new insights into efficient therapeutic strategies
C. Culmsee (2007)
10.4236/JBPC.2010.13019
Antioxidative action of N--tosyl-L-lysine chloromethyl ketone prevents death of glutathione-depleted cardiomyocytes induced by hydrogen peroxide
K. Takahashi (2010)
10.1038/cdd.2011.96
Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012
L. Galluzzi (2012)
10.1002/jcb.21550
Serine protease inhibitors N‐α‐Tosyl‐L‐Lysinyl‐Chloromethylketone (TLCK) and N‐Tosyl‐L‐Phenylalaninyl‐Chloromethylketone (TPCK) are potent inhibitors of activated caspase proteases
I. Frydrych (2008)
10.1007/s00018-007-7288-3
Trypsin and trypsin-like proteases in the brain: Proteolysis and cellular functions
Y. Wang (2007)
10.1038/sj.cdd.4400859
Triggering of apoptosis by cathepsins
M. Leist (2001)
Apoptotic cell death induced by intracellular proteolysis.
M. S. Williams (1994)
10.1097/00004647-199808000-00001
Protective Effect of Apoptosis-Inhibitory Agent, N-Tosyl-l-Phenylalanyl Chloromethyl Ketone against Ischemia-Induced Hippocampal Neuronal Damage
A. Hara (1998)
10.1038/35040009
Apoptosis in neurodegenerative disorders
M. Mattson (2000)
10.1016/0014-5793(95)00370-O
Involvement of multiple proteases during Fas‐mediated apoptosis in T lymphocytes
S. C. Chow (1995)
10.1074/JBC.M008944200
Lysosomal Protease Pathways to Apoptosis
V. Stoka (2001)
10.1038/nature05292
Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases
M. Lin (2006)
10.1038/cdd.2008.78
Bid-induced release of AIF from mitochondria causes immediate neuronal cell death
S. Landshamer (2008)
Involvement of both caspase-like proteases and serine proteases in apoptotic cell death Apoptosis
N Komatsu (1998)
10.1016/0008-8749(87)90240-1
Protection from tumor necrosis factor cytotoxicity by protease inhibitors.
V. Ruggiero (1987)
10.1101/gad.1658508
Mitochondrial dynamics and apoptosis.
Der-Fen Suen (2008)
N-alpha-Tosyl-L-lysine chloromethyl ketone and N-alpha-tosyl-L-phenylalanine chloromethyl ketone inhibit protein kinase C.
D. H. Solomon (1985)
10.1038/nrn2665
Mitochondrial membrane permeabilization in neuronal injury
L. Galluzzi (2009)
10.1016/S0306-4522(01)00322-0
Inhibitors of trypsin-like serine proteases prevent DNA damage-induced neuronal death by acting upstream of the mitochondrial checkpoint and of p53 induction
H. Rideout (2001)
10.1038/sj.onc.1207512
Lysosomes in cell death
M. E. Guicciardi (2004)
10.1016/S0166-2236(97)01188-0
Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity
M. Mattson (1998)
10.1016/j.intimp.2013.03.019
Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat.
Yueyu Hu (2013)
10.1152/AJPLUNG.2001.281.3.L556
Serine proteases increase oxidative stress in lung cells.
K. Aoshiba (2001)
10.1038/sj.cgt.7700867
Targeted gene therapy for breast cancer with truncated Bid
I. Kazhdan (2006)
10.1167/iovs.09-3381
Enhanced HtrA2/Omi expression in oxidative injury to retinal pigment epithelial cells and murine models of neurodegeneration.
X. Ding (2009)
10.1038/labinvest.3780222
Relocalization of Cathepsin D and Cytochrome c Early in Apoptosis Revealed by Immunoelectron Microscopy
K. Roberg (2001)
10.1189/jlb.0506359
Cathepsin‐cleaved Bid promotes apoptosis in human neutrophils via oxidative stress‐induced lysosomal membrane permeabilization
R. Blomgran (2007)
10.1093/OXFORDJOURNALS.JBCHEM.A022197
Involvement of both caspase-like proteases and serine proteases in apoptotic cell death induced by ricin, modeccin, diphtheria toxin, and pseudomonas toxin.
N. Komatsu (1998)



This paper is referenced by
Semantic Scholar Logo Some data provided by SemanticScholar