Skip to main content
SpringerLink
Log in

Proteases in Death Pathways

  • Chapter
  • First Online:
Proteases: Structure and Function

Abstract

Caspases are the essential proteases in cellular death pathways and well known as the key players during apoptosis. They are involved in the initiation and execution of the extrinsic and caspase-dependent intrinsic apoptotic pathways as well as in pyroptotic cell deletion. After a short introduction about different cell death modalities, we will have a closer look at these important enzymes that belong to one of the best-characterized protease families.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Aβ:

Amyloid-β

AIF:

Apoptosis-inducing factor

Apaf-1:

Apoptotic protease activating factor 1

APP:

Amyloid precursor protein

BH:

Bcl-2 homology

Bid:

BB3-interacting domain

BIR:

Baculoviral IAP repeat

C. elegans :

Caenorhabditis elegans

CAD:

Caspase-activated DNAse

CARD:

Caspase activation and recruitment domain

DAMP:

danger associated molecular pattern

DARPin:

Designed ankyrin repeat protein

DD:

Death domain

DED:

Death effector domain

DFF40:

DNA fragmentation factor 40 also termed CAD

DIABLO:

Direct IAP binding protein with low pI, also termed Smac

DISC:

Death-inducing signaling complex

ENDOG:

Endonuclease g

FADD:

Fas-associated death domain

FLICE:

FADD-like interleukin-1 beta-converting enzyme, today known as caspase-8

FLIP:

FLICE-inhibitory protein

HTRA2:

High temperature requirement protein 2

htt:

Huntingtin

IAP:

Inhibitor of apoptosis protein

ICAD:

Inhibitor of CAD, also known as DFF45

ICE:

Interleukin-1β-converting enzyme

IMS:

Inter-membrane space

LRR:

Leucine-rich repeat

MOMP:

Mitochondrial outer membrane permeabilization

NC-IUBMB:

Nomenclature Committee of the International Union of Biochemistry and Molecular Biology

NCCD:

Nomenclature Committee on Cell Death

NFT:

Neurofibrillary tangle

NLR:

NOD-like receptor

NOD:

Nucleotide binding and oligomerization domain

PARP:

Poly(ADP-ribose) polymerase

PIDD:

p53-induced protein with a death domain

PS:

Phosphatidylserine

RIP:

Receptor-interacting protein

ROCK:

Rho-associated kinase

Smac:

Second mitochondria-derived activator of caspase, also termed DIABLO

tBid:

Truncated Bid

TNF:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

UBA:

Ubiquitin associated

XIAP:

X-linked inhibitor of apoptosis protein

References

  • Agard NJ, Wells JA (2009) Methods for the proteomic identification of protease substrates. Curr Opin Chem Biol 13(5–6):503–509

    CAS  PubMed Central  PubMed  Google Scholar 

  • Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20(3):319–325

    CAS  PubMed  Google Scholar 

  • Akita K, Ohtsuki T, Nukada Y, Tanimoto T, Namba M, Okura T, Takakura-Yamamoto R, Torigoe K, Gu Y, Su MS, Fujii M, Satoh-Itoh M, Yamamoto K, Kohno K, Ikeda M, Kurimoto M (1997) Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells. J Biol Chem 272(42):26595–26603

    CAS  PubMed  Google Scholar 

  • Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5(7):647–654

    CAS  PubMed  Google Scholar 

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87(2):171

    CAS  PubMed  Google Scholar 

  • Alvarado-Kristensson M, Melander F, Leandersson K, Rönnstrand L, Wernstedt C, Andersson T (2004) p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J Exp Med 199(4):449–458

    CAS  PubMed Central  PubMed  Google Scholar 

  • Binz HK, Amstutz P, Kohl A, Stumpp MT, Briand C, Forrer P, Grütter MG, Plückthun A (2004) High-affinity binders selected from designed ankyrin repeat protein libraries. Nat Biotechnol 22(5):575–582

    CAS  PubMed  Google Scholar 

  • Boyd SE, Pike RN, Rudy GB, Whisstock JC, Garcia de la Banda M (2005) PoPS: a computational tool for modeling and predicting protease specificity. J Bioinform Comput Biol 3(3):551–585

    CAS  PubMed  Google Scholar 

  • Bratton SB, Lewis J, Butterworth M, Duckett CS, Cohen GM (2002) XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ 9(9):881–892

    CAS  PubMed  Google Scholar 

  • Brennan MA, Cookson BT (2000) Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 38(1):31–40

    CAS  PubMed  Google Scholar 

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282(5392):1318–1321

    CAS  PubMed  Google Scholar 

  • Center DM, Cruikshank WW, Zhang Y (2004) Nuclear pro-IL-16 regulation of T cell proliferation: p27(KIP1)-dependent G0/G1 arrest mediated by inhibition of Skp2 transcription. J Immunol 172(3):1654–1660

    CAS  PubMed  Google Scholar 

  • Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y, Dataa P (2001a) Structural basis of caspase-7 inhibition by XIAP. Cell 104(5):769–780

    CAS  PubMed  Google Scholar 

  • Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y (2001b) Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding. Cell 107(3):399–407

    CAS  PubMed  Google Scholar 

  • Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S, Peter ME, Yang X (2002) c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J 21(14):3704–3714

    CAS  PubMed  Google Scholar 

  • Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L (1997) Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 7(6):821–830

    CAS  PubMed  Google Scholar 

  • Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81(4):505–512

    CAS  PubMed  Google Scholar 

  • Chodorge M, Züger S, Stirnimann C, Briand C, Jermutus L, Grütter MG, Minter RR (2012) A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency. Cell Death Differ 19(7):1187–1195

    CAS  PubMed  Google Scholar 

  • Chupp GL, Wright EA, Wu D, Vallen-Mashikian M, Cruikshank WW, Center DM, Kornfeld H, Berman JS (1998) Tissue and T cell distribution of precursor and mature IL-16. J Immunol 161(6):3114–3119

    CAS  PubMed  Google Scholar 

  • Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3(4):339–345

    CAS  PubMed  Google Scholar 

  • Conradt B, Horvitz HR (1998) The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93(4):519–529

    CAS  PubMed  Google Scholar 

  • Cookson BT, Brennan MA (2001) Pro-inflammatory programmed cell death. Trends Microbiol 9(3):113–114

    CAS  PubMed  Google Scholar 

  • Cooper DM, Pio F, Thi EP, Theilmann D, Lowenberger C (2007) Characterization of Aedes Dredd: a novel initiator caspase from the yellow fever mosquito, Aedes aegypti. Insect Biochem Mol Biol 37(6):559–569

    CAS  PubMed  Google Scholar 

  • de Alba E (2009) Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). J Biol Chem 284(47):32932–32941

    PubMed  Google Scholar 

  • Denault J-B, Salvesen GS (2003) Human caspase-7 activity and regulation by its N-terminal peptide. J Biol Chem 278(36):34042–34050

    CAS  PubMed  Google Scholar 

  • Denecker G, Ovaere P, Vandenabeele P, Declercq W (2008) Caspase-14 reveals its secrets. J Cell Biol 180(3):451–458

    CAS  PubMed  Google Scholar 

  • Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388(6639):300–304

    CAS  PubMed  Google Scholar 

  • Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17(8):2215–2223

    CAS  PubMed  Google Scholar 

  • Duan H, Dixit VM (1997) RAIDD is a new ‘death’ adaptor molecule. Nature 385(6611):86–89

    CAS  PubMed  Google Scholar 

  • Eckhart L, Ballaun C, Hermann M, VandeBerg JL, Sipos W, Uthman A, Fischer H, Tschachler E (2008) Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire. Mol Biol Evol 25(5):831–841

    CAS  PubMed  Google Scholar 

  • Ehrnhoefer DE, Sutton L, Hayden MR (2011) Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17(5):475–492

    CAS  PubMed Central  PubMed  Google Scholar 

  • Elliott JM, Rouge L, Wiesmann C, Scheer JM (2009) Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation. J Biol Chem 284(10):6546–6553

    CAS  PubMed  Google Scholar 

  • Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6):817–829

    CAS  PubMed  Google Scholar 

  • Faustin B, Lartigue L, Bruey J-M, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC (2007) Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 25(5):713–724

    CAS  PubMed  Google Scholar 

  • Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V (2012) Role of apoptosis in disease. Aging 4(5):330–349

    CAS  PubMed Central  PubMed  Google Scholar 

  • Flemming W (1885) Ueber die Bildung von Richtungsfiguren in Säugethiereiern beim Untergang Graaf’scher Follikel. Arch Anat Entw Gesch (Veit & Comp). 221–244

    Google Scholar 

  • Fuentes-Prior P, Salvesen GS (2004) The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 384(Pt 2):201–232

    CAS  PubMed  Google Scholar 

  • Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11(2):109–124

    CAS  PubMed  Google Scholar 

  • Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon H-U, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19(1):107–120

    CAS  PubMed  Google Scholar 

  • Germain M, Affar EB, D’Amours D, Dixit VM, Salvesen GS, Poirier GG (1999) Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem 274(40):28379–28384

    CAS  PubMed  Google Scholar 

  • Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN (2005) c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem 280(15):14507–14513

    CAS  PubMed  Google Scholar 

  • Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125(6):1179–1191

    CAS  PubMed  Google Scholar 

  • Graham RK, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi MA, Metzler M, Bissada N, Wang L, Faull RLM, Gray M, Yang XW, Raymond LA, Hayden MR (2010) Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci 30(45):15019–15029

    CAS  PubMed Central  PubMed  Google Scholar 

  • Graham RK, Ehrnhoefer DE, Hayden MR (2011) Caspase-6 and neurodegeneration. Trends Neurosci 34(12):646–656

    CAS  PubMed  Google Scholar 

  • Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS (2011) RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell 44(1):9–16

    CAS  PubMed Central  PubMed  Google Scholar 

  • Grimsley C, Ravichandran KS (2003) Cues for apoptotic cell engulfment: eat-me, don’t eat-me and come-get-me signals. Trends Cell Biol 13(12):648–656

    CAS  PubMed  Google Scholar 

  • Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275(5297):206–209

    CAS  PubMed  Google Scholar 

  • Hackam AS, Singaraja R, Wellington CL, Metzler M, McCutcheon K, Zhang T, Kalchman M, Hayden MR (1998) The influence of huntingtin protein size on nuclear localization and cellular toxicity. J Cell Biol 141(5):1097–1105

    CAS  PubMed  Google Scholar 

  • Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279(5350):509–514

    CAS  PubMed  Google Scholar 

  • Hanes J, Plückthun A (1997) In vitro selection and evolution of functional proteins by using ribosome display. Proc Natl Acad Sci U S A 94(10):4937–4942

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hardwick JM, Chen Y-b, Jonas EA (2012) Multipolar functions of BCL-2 proteins link energetics to apoptosis. Trends Cell Biol 22(6):318–328

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hardy JA, Lam J, Nguyen JT, O’Brien T, Wells JA (2004) Discovery of an allosteric site in the caspases. Proc Natl Acad Sci U S A 101(34):12461–12466

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hengartner MO, Ellis RE, Horvitz HR (1992) Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356(6369):494–499

    CAS  PubMed  Google Scholar 

  • Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135(7):1311–1323

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoste E, Denecker G, Gilbert B, Van Nieuwerburgh F, van der Fits L, Asselbergh B, De Rycke R, Hachem J-P, Deforce D, Prens EP, Vandenabeele P, Declercq W (2013) Caspase-14-deficient mice are more prone to the development of parakeratosis. J Invest Dermatol 133(3):742–750

    CAS  PubMed  Google Scholar 

  • Huang W-X, Huang P, Hillert J (2004) Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis. Mult Scler 10(5):482–487

    CAS  PubMed  Google Scholar 

  • Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, Macfarlane M (2009) Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival. Mol Cell 35(3):265–279

    CAS  PubMed  Google Scholar 

  • Javle M, Curtin NJ (2011) The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer 105(8):1114–1122

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC (2008) Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8. J Biol Chem 283(9):5402–5413

    CAS  PubMed  Google Scholar 

  • Kamens J, Paskind M, Hugunin M, Talanian RV, Allen H, Banach D, Bump N, Hackett M, Johnston CG, Li P (1995) Identification and characterization of ICH-2, a novel member of the interleukin-1 beta-converting enzyme family of cysteine proteases. J Biol Chem 270(25):15250–15256

    CAS  PubMed  Google Scholar 

  • Kavuri SM, Geserick P, Berg D, Dimitrova DP, Feoktistova M, Siegmund D, Gollnick H, Neumann M, Wajant H, Leverkus M (2011) Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signaling complex. J Biol Chem 286(19):16631–16646

    CAS  PubMed  Google Scholar 

  • Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479(7371):117–121

    CAS  PubMed  Google Scholar 

  • Keller N, Mares J, Zerbe O, Grütter MG (2009) Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation. Structure 17(3):438–448

    CAS  PubMed  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239–257

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kersse K, Verspurten J, Vanden Berghe T, Vandenabeele P (2011) The death-fold superfamily of homotypic interaction motifs. Trends Biochem Sci 36(10):541–552

    CAS  PubMed  Google Scholar 

  • Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14(22):5579–5588

    CAS  PubMed  Google Scholar 

  • Kitazumi I, Tsukahara M (2011) Regulation of DNA fragmentation: the role of caspases and phosphorylation. FEBS J 278(3):427–441

    CAS  PubMed  Google Scholar 

  • Koenig U, Eckhart L, Tschachler E (2001) Evidence that caspase-13 is not a human but a bovine gene. Biochem Biophys Res Commun 285(5):1150–1154

    CAS  PubMed  Google Scholar 

  • Krijnen PAJ, Sipkens JA, Molling JW, Rauwerda JA, Stehouwer CDA, Muller A, Paulus WJ, van Nieuw Amerongen GP, Hack CE, Verhoeven AJ, van Hinsbergh VWM, Niessen HWM (2010) Inhibition of Rho-ROCK signaling induces apoptotic and non-apoptotic PS exposure in cardiomyocytes via inhibition of flippase. J Mol Cell Cardiol 49(5):781–790

    CAS  PubMed  Google Scholar 

  • Krippner-Heidenreich A, Talanian RV, Sekul R, Kraft R, Thole H, Ottleben H, Lüscher B (2001) Targeting of the transcription factor Max during apoptosis: phosphorylation-regulated cleavage by caspase-5 at an unusual glutamic acid residue in position P1. Biochem J 358(Pt 3):705–715

    CAS  PubMed  Google Scholar 

  • Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S (2001) Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem 276(23):20633–20640

    CAS  PubMed  Google Scholar 

  • Kumar S, Doumanis J (2000) The fly caspases. Cell Death Differ 7(11):1039–1044

    CAS  PubMed  Google Scholar 

  • Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111(3):331–342

    CAS  PubMed  Google Scholar 

  • Lamkanfi M, Walle LV, Kanneganti T-D (2011) Deregulated inflammasome signaling in disease. Immunol Rev 243(1):163–173

    PubMed Central  PubMed  Google Scholar 

  • Larsen BD, Rampalli S, Burns LE, Brunette S, Dilworth FJ, Megeney LA (2010) Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc Natl Acad Sci U S A 107(9):4230–4235

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371(6495):346–347

    CAS  PubMed  Google Scholar 

  • Lewis EM, Wilkinson AS, Davis NY, Horita DA, Wilkinson JC (2011) Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation. Biochemistry 50(51):11084–11096

    CAS  PubMed  Google Scholar 

  • Lüthi AU, Cullen SP, Mcneela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, Lavelle EC, Martin SJ (2009) Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31(1):84–98

    PubMed  Google Scholar 

  • Mandal D, Moitra PK, Saha S, Basu J (2002) Caspase 3 regulates phosphatidylserine externalization and phagocytosis of oxidatively stressed erythrocytes. FEBS Lett 513(2–3):184–188

    CAS  PubMed  Google Scholar 

  • Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430(6996):213–218

    CAS  PubMed  Google Scholar 

  • Martin DA, Siegel RM, Zheng L, Lenardo MJ (1998) Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal. J Biol Chem 273(8):4345–4349

    CAS  PubMed  Google Scholar 

  • Martin SJ, Henry CM, Cullen SP (2012) A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol Cell 46(4):387–397

    CAS  PubMed  Google Scholar 

  • Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117(5):561–574

    CAS  PubMed  Google Scholar 

  • Martinon F, Tschopp J (2005) NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26(8):447–454

    CAS  PubMed  Google Scholar 

  • Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426

    CAS  PubMed  Google Scholar 

  • McStay GP, Salvesen GS, Green DR (2008) Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways. Cell Death Differ 15(2):322–331

    CAS  PubMed  Google Scholar 

  • Meergans T, Hildebrandt AK, Horak D, Haenisch C, Wendel A (2000) The short prodomain influences caspase-3 activation in HeLa cells. Biochem J 349(Pt 1):135–140

    CAS  PubMed  Google Scholar 

  • Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, Leaf IA, Aderem A (2010) Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A 107(7):3076–3080

    CAS  PubMed Central  PubMed  Google Scholar 

  • Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grütter MG (2002) The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem 277(47):45162–45171

    CAS  PubMed  Google Scholar 

  • Nagata S, Nagase H, Kawane K, Mukae N, Fukuyama H (2003) Degradation of chromosomal DNA during apoptosis. Cell Death Differ 10(1):108–116

    CAS  PubMed  Google Scholar 

  • Oberst A, Dillon CP, Weinlich R, Mccormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471(7338):363–367

    CAS  PubMed Central  PubMed  Google Scholar 

  • Olsson M, Zhivotovsky B (2011) Caspases and cancer. Cell Death Differ 18(9):1441–1449

    CAS  PubMed  Google Scholar 

  • Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276(5309):111–113

    CAS  PubMed  Google Scholar 

  • Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H (2007) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128(3):533–546

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pop C, Timmer J, Sperandio S, Salvesen GS (2006) The apoptosome activates caspase-9 by dimerization. Mol Cell 22(2):269–275

    CAS  PubMed  Google Scholar 

  • Pop C, Fitzgerald P, Green DR, Salvesen GS (2007) Role of proteolysis in caspase-8 activation and stabilization. Biochemistry 46(14):4398–4407

    CAS  PubMed  Google Scholar 

  • Qi S, Pang Y, Hu Q, Liu Q, Li H, Zhou Y, He T, Liang Q, Liu Y, Yuan X, Luo G, Li H, Wang J, Yan N, Shi Y (2010) Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4. Cell 141(3):446–457

    CAS  PubMed  Google Scholar 

  • Rao L, Perez D, White E (1996) Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol 135(6 Pt 1):1441–1455

    CAS  PubMed  Google Scholar 

  • Rathinam VAK, Vanaja SK, Fitzgerald KA (2012) Regulation of inflammasome signaling. Nat Immunol 13(4):333–342

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40:D343–D350

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reubold TF, Wohlgemuth S, Eschenburg S (2011) Crystal structure of full-length Apaf-1: how the death signal is relayed in the mitochondrial pathway of apoptosis. Structure 19(8):1074–1083

    CAS  PubMed  Google Scholar 

  • Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Salvesen GS, Bode W (2001a) Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci U S A 98(26):14790–14795

    CAS  PubMed Central  PubMed  Google Scholar 

  • Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS (2001b) Structural basis for the inhibition of caspase-3 by XIAP. Cell 104(5):791–800

    CAS  PubMed  Google Scholar 

  • Rohn TT (2010) The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities. Apoptosis 15(11):1403–1409

    CAS  PubMed  Google Scholar 

  • Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie L-A, Head E (2008) Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 28(12):3051–3059

    CAS  PubMed  Google Scholar 

  • Roschitzki-Voser H, Schroeder T, Lenherr ED, Frölich F, Schweizer A, Donepudi M, Ganesan R, Mittl PRE, Baici A, Grütter MG (2012) Human caspases in vitro: expression, purification and kinetic characterization. Protein Expr Purif 84(2):236–246

    CAS  PubMed  Google Scholar 

  • Rubinsztein DC, Shpilka T, Elazar Z (2012) Mechanisms of autophagosome biogenesis. Curr Biol 22(1):R29–R34

    CAS  PubMed  Google Scholar 

  • Safa AR (2012) c-FLIP, a master anti-apoptotic regulator. Exp Oncol 34(3):176–184

    CAS  PubMed  Google Scholar 

  • Sahoo M, Ceballos-Olvera I, Del Barrio L, Re F (2011) Role of the inflammasome, IL-1β, and IL-18 in bacterial infections. Scientific World J 11:2037–2050

    CAS  Google Scholar 

  • Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG, Zehnbauer BA, Hayden MR, Farrer LA, Roy S, Nicholson DW (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429(6987):75–79

    CAS  PubMed  Google Scholar 

  • Salvesen GS, Dixit VM (1999) Caspase activation: the induced-proximity model. Proc Natl Acad Sci U S A 96(20):10964–10967

    CAS  PubMed Central  PubMed  Google Scholar 

  • Scaffidi C, Schmitz I, Krammer PH, Peter ME (1999) The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274(3):1541–1548

    CAS  PubMed  Google Scholar 

  • Schile AJ, García-Fernández M, Steller H (2008) Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev 22(16):2256–2266

    CAS  PubMed  Google Scholar 

  • Schroeder T, Barandun J, Flütsch A, Briand C, Mittl PRE, Grütter MG (2013) Specific inhibition of caspase-3 by a competitive DARPin: molecular mimicry between native and designed inhibitors. Structure 21(2):277–289

    CAS  PubMed  Google Scholar 

  • Schweizer A, Roschitzki-Voser H, Amstutz P, Briand C, Gulotti-Georgieva M, Prenosil E, Binz HK, Capitani G, Baici A, Plückthun A, Grütter MG (2007) Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, structure, and inhibition mechanism. Structure 15(5):625–636

    CAS  PubMed  Google Scholar 

  • Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457(7232):1019–1022

    CAS  PubMed Central  PubMed  Google Scholar 

  • Seeger MA, Mittal A, Velamakanni S, Hohl M, Schauer S, Salaa I, Grütter MG, Van Veen HW (2012) Tuning the drug efflux activity of an ABC transporter in vivo by in vitro selected DARPin binders. PLoS One 7(6):e37845

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y (2003) Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell 11(2):519–527

    CAS  PubMed  Google Scholar 

  • Soares J, Lowe MM, Jarstfer MB (2011) The catalytic subunit of human telomerase is a unique caspase-6 and caspase-7 substrate. Biochemistry 50(42):9046–9055

    CAS  PubMed  Google Scholar 

  • Sollberger G, Strittmatter GE, Kistowska M, French LE, Beer H-D (2012) Caspase-4 is required for activation of inflammasomes. J Immunol 188(4):1992–2000

    CAS  PubMed  Google Scholar 

  • Steiner D, Forrer P, Plückthun A (2008) Efficient selection of DARPins with sub-nanomolar affinities using SRP phage display. J Mol Biol 382(5):1211–1227

    CAS  PubMed  Google Scholar 

  • Steller H (2008) Regulation of apoptosis in Drosophila. Cell Death Differ 15(7):1132–1138

    CAS  PubMed  Google Scholar 

  • Stennicke HR, Deveraux QL, Humke EW, Reed JC, Dixit VM, Salvesen GS (1999) Caspase-9 can be activated without proteolytic processing. J Biol Chem 274(13):8359–8362

    CAS  PubMed  Google Scholar 

  • Suzuki Y, Nakabayashi Y, Takahashi R (2001) Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci U S A 98(15):8662–8667

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schröter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386(6624):517–521

    CAS  PubMed  Google Scholar 

  • Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J (1992) A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356(6372):768–774

    CAS  PubMed  Google Scholar 

  • Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M, Houtzager VM, Nordstrom PA, Roy S, Vaillancourt JP, Chapman KT, Nicholson DW (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 272(29):17907–17911

    CAS  PubMed  Google Scholar 

  • Timmer JC, Salvesen GS (2007) Caspase substrates. Cell Death Differ 14(1):66–72

    CAS  PubMed  Google Scholar 

  • Tinel A, Tschopp J (2004) The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304(5672):843–846

    CAS  PubMed  Google Scholar 

  • Tinel A, Janssens S, Lippens S, Cuenin S, Logette E, Jaccard B, Quadroni M, Tschopp J (2007) Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. EMBO J 26(1):197–208

    CAS  PubMed  Google Scholar 

  • Tsiatsiani L, Van Breusegem F, Gallois P, Zavialov A, Lam E, Bozhkov PV (2011) Metacaspases. Cell Death Differ 18(8):1279–1288

    CAS  PubMed  Google Scholar 

  • Vaughn DE, Rodriguez J, Lazebnik Y, Joshua-Tor L (1999) Crystal structure of Apaf-1 caspase recruitment domain: an alpha-helical Greek key fold for apoptotic signaling. J Mol Biol 293(3):439–447

    CAS  PubMed  Google Scholar 

  • Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6(4):287–297

    CAS  PubMed  Google Scholar 

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102(1):43–53

    CAS  PubMed  Google Scholar 

  • Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277(1):445–454

    CAS  PubMed  Google Scholar 

  • Vucic D, Franklin MC, Wallweber HJA, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ (2005) Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J 385(Pt 1):11–20

    CAS  PubMed  Google Scholar 

  • Vucic D, Dixit VM, Wertz IE (2011) Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12(7):439–452

    CAS  PubMed  Google Scholar 

  • Wachmann K, Pop C, Van Raam BJ, Drag M, Mace PD, Snipas SJ, Zmasek C, Schwarzenbacher R, Salvesen GS, Riedl SJ (2010) Activation and specificity of human caspase-10. Biochemistry 49(38):8307–8315

    CAS  PubMed Central  PubMed  Google Scholar 

  • Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT (1997) TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16(17):5386–5397

    CAS  PubMed  Google Scholar 

  • Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H (2010) The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17(11):1324–1329

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA (1994) Structure and mechanism of interleukin-1 beta converting enzyme. Nature 370(6487):270–275

    CAS  PubMed  Google Scholar 

  • Yang Z, Klionsky DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335:1–32

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ (1999) Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400(6747):886–891

    CAS  PubMed  Google Scholar 

  • Yu JW, Jeffrey PD, Shi Y (2009) Mechanism of procaspase-8 activation by c-FLIPL. Proc Natl Acad Sci U S A 106(20):8169–8174

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75(4):641–652

    CAS  PubMed  Google Scholar 

  • Yuan S, Yu X, Topf M, Ludtke SJ, Wang X, Akey CW (2010) Structure of an apoptosome-procaspase-9 CARD complex. Structure 18(5):571–583

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan S, Yu X, Asara JM, Heuser JE, Ludtke SJ, Akey CW (2011) The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3. Structure 19(8):1084–1096

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Y-w, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Y, Center DM, Wu DM, Cruikshank WW, Yuan J, Andrews DW, Kornfeld H (1998) Processing and activation of pro-interleukin-16 by caspase-3. J Biol Chem 273(2):1144–1149

    CAS  PubMed  Google Scholar 

  • Ziegler U, Groscurth P (2004) Morphological features of cell death. News Physiol Sci 19:124–128

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by the Swiss National Science Foundation grant 310030-122342 to Markus G. Grütter.

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zürich, Switzerland

    Andreas Flütsch & Markus G. Grütter

Authors
  1. Andreas Flütsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus G. Grütter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus G. Grütter .

Editor information

Editors and Affiliations

  1. SCHOOL OF ENGINEERING AND SCIENCE, JACOBS UNIVERSITY BREMEN, Bremen, Germany

    Klaudia Brix

  2. Institute of Zoology, Johannes Gutenberg University Mainz, Mainz, Germany

    Walter Stöcker

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Wien

About this chapter

Cite this chapter

Flütsch, A., Grütter, M.G. (2013). Proteases in Death Pathways. In: Brix, K., Stöcker, W. (eds) Proteases: Structure and Function. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0885-7_8

Download citation

Publish with us

Policies and ethics

Search

Navigation