MOLECULAR CONTROL OF APOPTOSIS. CRCHUM- R
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1 MOLECULAR CONTROL OF APOPTOSIS CRCHUM- R
2 APOPTOSIS AND DISEASES Cell proliferation Cell death Normal Homeostasis Alterations Excessive cell death Deficient cell death
3 Neurodenenerative disorders Alzheimer's disease Parkinson's disease Huntington's disease Amyotrophic lateral sclerosis Spinal muscular atrophy Retinis pigmentosa Infectous diseases AIDS Fulmunant Hepatitis B & C Polycystic kidney disease Hypertension Haematological diseases Myelodysplasia syndromes Aplastic anemia Chronic neutropenia Severe B-thalassaemia Excessive cell death Toxin-induced liver disease Alcohol Ischemic injury Myocardial infarction Stroke Reperfusion injury
4 CANCERS Autoimmune disorders Systemic lupus erythematosus Rheumatoid arthritis Autoimmune diabetes mellitus Lymphadenopathy Glomerulonephritis Deficient cell death Neurodevelopmental disorders Autism?? Fragile X syndrome?? Schizophrenia?? Viral latency EBV (mononucleosis + cancer) Herpesviruses Poxviruses Adenoviruses
5 MORPHOLOGIC CRITERIA APOPTOSIS DELETION OF SINGLE CELLS MEMBRANE INTEGRITY CELL SHRINKAGE APOPTOTIC BODIES (BLEBBING) PHAGOCYTOSIS BY ADJACENT CELLS CHROMATIN CONDENSATION AND ORDERED DNA FRAGMENTATION NO INFLAMMATORY RESPONSE INDUCED BY PHYSIOLOGICAL STIMULI NECROSIS DEATH OF CELL GROUP LOST OF MEMBRANE INTEGRITY CELL SWELLING NO BLEBBING - CELL LYSIS PHAGOCYTOSIS BY MACROPHAGES RANDOM DIGESTION OF DNA INFLAMMATORY RESPONSE «NON-PHYSIOLOGICAL» STIMULI
6 SCHEMATIC REPRESENTATION OF A CELL UNDERGOING APOPTOSIS
7
8 GENETIC CONTROL OF PROGRAMMED CELL DEATH IN THE NEMATODE CAENORHABDITIS ELEGANS Pro-apoptotic Anti-apoptotic Activator Effector Morphological changes Engulfment Elimination Egl-1 Ced-13 Ced-9 ces-2 ces-1 cyt-1 Ced-4 Ced-3 Ced-8 Ced-11 Icd-1 Ced-1 Ced-6 Ced-7 Ced-2 Ced-5 Ced-10 Ced-12 Nuc-1 Wah-1 Cps-6 Hermaphrodite: 1090 cells Nematode: 959 cells
9 MOLECULAR FRAMEWORK OF APOPTOSIS IN C. ELEGANS Ced-13 Egl-1 Ced-9 Mitochondria Ced-4 Ced-4 Ced-3 Ced-3 cell death
10 C. elegans H. Sapiens Ced-9 Egl-1 Bcl-2 / Bcl-xL BH3-only <sensitizer> Ced-4 Apaf-1 Bax / Bak BH3-only <activator> Ced-3 Caspase-9 APOPTOSE APOPTOSE
11 Ced-9 - Egl-1 or Ced-13 orthologs in mammals
12 Mammalian Ced-9/Egl-1/Bcl-2 like Family PFD BH-4 LoopD BH-3 BH-1 BH-2 TM Hydrophobic ced-9 Anti-apoptotic Bcl-2 Bcl-xL Bcl-w Mcl-1 A-1/Bfl-1/Grs Boo/Diva Brag-1 Bcl-xES Bcl-B Bcl-2-L-10 ced-9 Pro-apoptotic Bax Bak Bcl-xS Mtd/Bok Bcl-rambo Bcl-gL egl-1/ced-13 Pro-apoptotic ( BH-3 only ) Bik/Nbk/mBlk Bid Hrk / Dp5 Bad Bim/Bod Bnip3 - Bnip3L/Nix Bnip1 - Bnip1b Noxa Map-1 Bcl-gS Puma/ Bbc3 Bmf Mcl-1s Spike Itm2Bs Apo6L
13 Bcl-xL structure -function BH4 LOOP BH3 BH1 BH2 TM α-1 α-2 α-3 α-4 α-5 α-6 α-7/8 α FSDVEENRTEAPEG TESEMETPSAINGNPSWHLADSPA VNGATGHSSSLDAREVIP Bcl-xL 3D structure (TM) ACTIVE GROOVE BH3 BH2 BH1 S S62 BH4 S49 S49 *modified from NCBI / cn3d
14 PFD BH4 loop BH3 BH1 BH2 TM Bcl-xL Bcl-2 Ced 9-like antiapoptotic PFD BH4 BH3 BH1 BH2 BH3 PFD BH1 BH2 TM Bcl-w Mcl-1 Boo/Diva Bcl-b ma1 \ Bfl-1 BH4 BH2 TM Bcl-xES Ced 9-like proapoptotic BH3 BH3 BH1 BH1 PFD BH2 PFD BH2 TM TM Bax-a Bak Mtd/Bok Bax-s PFD BH3 BH1 BH2 R R TM Bcl-rambo BH3 BH2 Bcl-g L BH4 loop BH3 TM Bcl-xS
15 Egl 1-like proapoptotic (BH3-only) BH3 BH3 TM Bik/Nbk/mBlk Bim/Bod Hrk/Dp5 BNip3 - BNip3L/Nix BNip1 Spike Bad Bid Map-1 Puma/ Bbc3 Bcl-gs Bmf Egl-1 Ced-13 BH3 BH3 Noxa
16 Bax isoforms PFD BH3 BH1 BH2 TM Bax-a PFD BH3 BH1 BH2 TM Bax-s BH3 BH1 PFD BH2 Bax-b BH3 BH1 PFD BH2 Bax-w BH3 BH1 Bax-e BH1 PFD BH2 TM Bax-d Bax-g, -k
17 bcl-x isoforms PFD BH4 loop BH3 BH1 BH2 TM bcl-xl BH4 BH2 TM bcl-xes BH4 loop BH3 TM bcl-xs
18 C. elegans H. Sapiens Ced-9 Egl-1 Bcl-2 / Bcl-xL BH3-only <sensitizer> Ced-4 Apaf-1 Bax / Bak BH3-only <activator> Ced-3 Caspase-9 APOPTOSE APOPTOSE
19 Ced-4 orthologs in mammals
20 Mammalian CED-4 Family members A B (Walker domain) WD repeat APAF-1 CARD CED-4 like DOMAIN - CARD-4 / NOD-1 - CLAN / CARD-12 - IAPAF CARD A B (Walker domain) CED-4 like DOMAIN A B (Walker domain) LRR repeat LRR repeat NOD-2 CARD CARD CED-4 like DOMAIN NAC / DEFCAP / CARD-7 PYR A B (Walker domain) CED-4 like DOMAIN LRR repeat CARD A (Walker-like domain) FLASH PACAP CED-4 like domain A B (Walker domain) CED-4 like DOMAIN DRD domain
21 Ced-3 orthologs in mammals
22 Mammalian CED3 or Procaspases DED* CARD** D QACXG D pro-enzyme inactive (procaspase) active enzyme (caspase) ICE-like Ice (5 iso)/ Casp 1 ** Ich-2/ Tx/IceRel II/ Casp 4 ** Ty/ IceRel III / Casp 5 ** mich-3 / Casp 11 ** mich-4/ Casp12 ** Erice/ Casp13 ** Viz/ Casp14 CPP32-like CPP32/Yama/Apopain/ Casp 3 Mch-2 / Casp 6 Mch-3/Ice-Lap 3/ CMH-1/ Casp 7 Mch-4/Flice-2 / Casp 10 * Mch-5/Flice/Mach/ Casp 8 * Nedd-like Ich-1 long/ short/ Casp 2 ** Mch-6/ Ice-Lap 6/ Casp9 **
23 ICE/caspase-1 homologs involved during inflammation Ced-3/caspase-3 homologs involved during apoptosis Casp-4 Casp-5 Casp-13 Casp-11 Casp-12 * Casp-1 Casp-14 Casp-3 Casp-7 Casp-6 Casp-8 Casp-10 Casp-9 Casp-2 effector caspases initiator caspases Biochimica et Biophysica Acta 1824 (2012)
24 MOLECULAR MODELS OF CASPASE ACTIVATION COMPLEXES (intrinsic pathway) Ced-13 BH3 BH3 Egl-1 Bcl-xL Bcl-2 Ced-9 Ced-4 Apaf-1 PIDD RAIDD Mitochondria Ced-3 ProCasp-9 ProCasp-2L Active Ced-3 Active Casp-9 Active Casp-2L (apoptosome) (piddosome)
25 Inhibitors of apoptosis (IAPs) in mammals
26 Mammalian IAP family members Most importants: BIR BIR BIR RING XIAP / MIHA BIR RING ILP-2 BIR RING KIAP / LIVIN Casp-3, -7 Procasp-9 BIR BIR BIR CARD RING ciap1 / MIHB BIR BIR BIR CARD RING ciap2 / MIHC (*ubiquitin ligase) BIR SURVIVIN Casp-3,-7 microtubules at telophase BIR BIR BIR NACHT LRR NIAP hippocalcin / Ca BIR UBC APOLLON / BRUCE ubiquitin-conjugating enzyme
27 Mammalian inhibitors of IAPs XAF1 Nuclear sequester protein of XIAP Diablo / Smac Release from mitochondria sequester of IAPs HTR-A2/ Omni Release from mitochondria sequester of IAPs serine protease activity
28 Cell death receptors and associated proteins in mammals
29 MAMMALIAN CELL DEATH RECEPTOR FAMILY Apo1L/FasL TNF-a Tweak/Apo-3L TL1A TrailL??? CD95/FAS * TNF-R1 DR-3 DR-4 * DR-5 * DR-6 SODD / BAG-4 DEATH DOMAIN * ALSO DECOY RECEPTORS WITHOUT DD
30 Molecular mechanisms of apoptosis activation in mammals
31 Death receptors Fas - TNF-R1 - DR3 -DR4 -DR5- DR6 Growth factors DISC FADD/MORT-1 Receptor TK PI3K procaspase-8 Bad Akt P Bad P Piddosome active caspase- 8 initiator Activation of effector caspases APOPTOSIS caspase-3 caspase-6, -2 caspase-7 IAPs IAPs Bid Omni/Htr 2A Diablo/Smac procaspase-9 tbid procaspase-9 IAPs Bcl-xL Apaf-1 Apaf-1 cytochrome c datp Bax Bak mptp swelling DYm Cytochrome c AIF active initiator caspase-9 Endo G Apoptosome RAIDD Procaspase-2L multiple BH3-only (noxa-puma-bim-bik-hrk..) DNA DAMAGE via cell death receptor Fas DR4 - DR5 PIDD via p53 / p63 / p73 E2F1 /Foxo3a via p53 / NFkB
32 TNFR : Survival Apoptosis - Necroptosis Current Opinion in Cell Biology 2010, 22:
33 Trends in Cell Biology November 2011, Vol. 21, No. 11
34 TNFR : Survival Apoptosis - Necroptosis GENES & DEVELOPMENT 27:
35 Death receptors Fas - TNF-R1 - DR3 -DR4 -DR5- DR6 Growth factors DISC FADD/MORT-1 Receptor TK PI3K procaspase-8 Bad Akt P Bad P Piddosome active caspase- 8 initiator Activation of effector caspases APOPTOSIS caspase-3 caspase-6, -2 caspase-7 IAPs IAPs Bid Omni/Htr 2A Diablo/Smac procaspase-9 tbid procaspase-9 IAPs Bcl-xL Apaf-1 Apaf-1 cytochrome c datp Bax Bak mptp swelling DYm Cytochrome c AIF active initiator caspase-9 Endo G Apoptosome RAIDD Procaspase-2L DNA DAMAGE via cell death receptor Fas DR4 DR5 PIDD multiple BH3-only (noxa-puma-bim-bik-hrk..) via p53 / p63 / p73 E2F1 /Foxo3a via p53 / NFkB
36 DNA strand breaks / Chromatin structure modification / Stalled replication fork ATM - ATR DNA strand break repairs IKK IkB NF-kB Ask-1 MKK3/6 p38 cabl MKK4/7 JNK-1, -2 AP-1 E2F1 Foxo3A p63 p73 p53 Gadd45 chk2 chk1 p21 cdc25a cdc25c cycline/cdk2 cyclina/cdk2 cyclinb/cdk1 G1 S G2 M SURVIVAL SIGNALS : via NF-kB and AP-1 / Bcl-2 Bcl-xL Mcl 1 Bcl-w - IAPs CELL DEATH SIGNALS : via p53 p63 p73 E2F1 Foxo3A / Bax Puma Noxa Bim Bik - Hrk / PIDD FAS DR4 -
37
38 Death receptors Fas - TNF-R1 - DR3 -DR4 -DR5- DR6 Growth factors DISC FADD/MORT-1 Receptor TK PI3K procaspase-8 Bad Akt P Bad P Piddosome active caspase- 8 initiator Activation of effector caspases APOPTOSIS caspase-3 caspase-6, -2 caspase-7 IAPs IAPs Bid Omni/Htr 2A Diablo/Smac procaspase-9 tbid procaspase-9 IAPs Bcl-xL Apaf-1 Apaf-1 cytochrome c datp Bax Bak mptp swelling DYm Cytochrome c AIF active initiator caspase-9 Endo G Apoptosome RAIDD Procaspase-2L DNA DAMAGE via cell death receptor Fas DR4 DR5 PIDD multiple BH3-only (noxa-puma-bim-bik-hrk..) via p53 / p63 / p73 E2F1 /Foxo3a via p53 / NFkB
39 DYm?? MAC Bak? Bcl-xL? Bax Bak DYm? Bax tbid sphingolipids ANT VDAC Bcl-2 Bcl-2 = apoptogenic factors Cytochrome c AIF Diablo/Smac Omi/HtrA2 EndoG Pro-caspases-2, -9? tbid ions ANT cardiolipids Bcl-xL DYm? Bax H 2 O DYm
40 Oligomeriztion and pore formation from Westphal et.al., Cell death Differ (2014) 21,
41 Death receptors Fas - TNF-R1 - DR3 -DR4 -DR5- DR6 Growth factors DISC FADD/MORT-1 Receptor TK PI3K procaspase-8 Bad Akt P Bad P Piddosome active caspase- 8 initiator Activation of effector caspases APOPTOSIS caspase-3 caspase-6, -2 caspase-7 IAPs IAPs Bid Omni/Htr 2A Diablo/Smac procaspase-9 tbid procaspase-9 IAPs Bcl-xL Apaf-1 Apaf-1 cytochrome c datp Bax Bak mptp swelling DYm Cytochrome c AIF active initiator caspase-9 Endo G Apoptosome RAIDD Procaspase-2L DNA DAMAGE via p53 / NFkB via cell death receptor Fas DR4 DR5 PIDD multiple BH3-only (noxa-puma-bim-bik-hrk..) via p53 / p63 / p73 E2F1 /Foxo3a
42 Caspase substrates (lost and gain of function) DNA fragmentation pathways Blebbing and apoptotic corpses Phagocytosis of apoptotic corpses
43 CASPASE SUBSTRATES (more than 800 listed )
44 VISUALIZATION OF DNA FRAGMENTATION hr hr Transverse alternating pulsed field electrophoresis Standard horizontal agarose gel electrophoresis
45 DNA FRAGMENTATION PATHWAYS ACTIVE CASPASE-9 ACINUS CASPASE-3, -7 NUCLEAR PORES AIF CHROMATIN CONDENSATION CASPASE-6,-2 High molecular weight DNA FRAGMENTATION NUCLEAR SCAFFOLD Endo G Oligonucleosome-size DNA FRAGMENTATION DFF40/CAD L-Dnase-II DFF45/ICAD DFF40/CAD ph LEI Dnase II (nuc-1) within phagocytes Ap24, An34, DNAs1l3, Nuc70, Nuc80, p97, Dnase g
46 APOPTOTIC CORPSE FORMATION and BLEBBING ACTIVE CASPASE-9 CYTOSKELETAL AND ADHESION PROTEINS CASPASE-3, -7 ACTIN GELSOLIN a-fodrin GAS 2 E-CADHERIN a-, b-, g- CATENINS a-, b-, SPECTRINS FILAMIN KINESIN EZRIN RADIXIN MOESIN KERATIN 18 blebs MCL PROTEIN KINASES MEKK-1 SLK MST-1, -2 PAK-2 ROCK-1 Calcium-independent phospholipase A2 Lyso-phosphatidylcholine (chemotatic signal)
47 PHAGOCYTOSIS TSP = trombospondin PS = phosphatidylserine LPC= lysophosphatidylcholine (chemotatic factor) Loss of salic acid SUGAR APOPTOTIC CORPSE TSP PS ABCA1 transporter (ced -7) LECTINS LPC Crk II (ced-2) ( SH2-SH3 ) Avb1, b3, b5 CD 36 PSR/CD14 SREC / LRP1 (ced-1) ABCA1 transporter (ced -7) TPBP/GULP (ced-6) Dock 180 ( ced-5) ANTI-INFLAMMATORY RESPONSE CYTOSKELETAL REMODELING ELMO ( ced-12) ( adaptor) Rac-1 ( ced-10) ( GTPase ) IL-8 TNFa IL-Ib IL-12 TGFb1 IL-10 PGE2
48 ???
49 Death receptors Fas - TNF-R1 - DR3 -DR4 -DR5- DR6 Growth factors DISC FADD/MORT-1 Receptor TK PI3K procaspase-8 Bad Akt P Bad P Piddosome active caspase- 8 initiator Activation of effector caspases APOPTOSIS caspase-3 caspase-6, -2 caspase-7 IAPs IAPs Bid Omni/Htr 2A Diablo/Smac procaspase-9 tbid procaspase-9 IAPs Bcl-xL Apaf-1 Apaf-1 cytochrome c datp Bax Bak mptp swelling DYm Cytochrome c AIF active initiator caspase-9 Endo G Apoptosome RAIDD Procaspase-2L DNA DAMAGE via cell death receptor Fas DR4 - DR5 PIDD multiple BH3-only (noxa-puma-bim-bik-hrk..) via p53 / p63 / p73 E2F1 /Foxo3a via p53 / NFkB
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