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Regulation of Apoptosis by BCL-2 Family Members (Prof. Thomas Kaufmann)
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Transcript of Regulation of Apoptosis by BCL-2 Family Members (Prof. Thomas Kaufmann)
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Regulation of Apoptosis by Bcl-2 Family Members
Thomas KaufmannInstitute of Pharmacology,
University of Bern , [email protected]
Vall d’Hebron Research InstituteNov 15 2012
and XIAP
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Necrosis Apoptosisvs.
2
passive, „accident“,always pathological
active, energy-dependent,physiological + pathophys.
often death of individualcells
whole (parts of) tissue/organ affected
induces inflammationno inflammation,induces tolerance
lysis of cellscells stay intact,
cleared by phagocytosis
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PROGRAMMED CELL DEATH
NECROTIC CELL DEATH“accidents”:- lack of energy- physical damage- chemical damage
Apoptosis
Autophagic Cell Death
Cornification(“keratinization”)
Pyroptosis(casp-1)
Pyronecrosis
Necroptosis(RIPK1/3)
Anoikis
3
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BCL-2, follicular lymphoma
Tumour Cells Overexpress Anti-Apoptotic Genes
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Follicular Lymphoma (spleen): t(14;18) IgH(14q32) BCL2(18q21)
mantle zone
germinal centre
BCL-2, control
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Effector Caspases(-3, -6 + -7)
Bax/Bak
cytochrome.c Caspase-9/Apaf-1
Bcl-2-like
Apoptosome
BH3-only proteins
cytokine deprivation, DNA- damage, hypoxia, viral infections, ER stress,anoikis, …
XIAP
(Bim, Puma, Bad,...)
(Bcl-2, Mcl-1,Bcl-xL, ...)
XIAP
tBid
Bidcaspase-8
procaspase-8 (-10)
DISC
cFLIPcIAP1/2
Death Receptor (Extrinsic Pathway)
Intrinsic Pathway
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The Bcl-2 Protein Family Regulates the Integrity of the Mitochondrial Outer Membrane
Bax-like
adaptor (APAF-1)
Bcl-2-like
BH3-only
Caspase-9
Bcl-2 Family
Cyt.cSmac/Diablo
XIAP
Caspase-3, -7 (, -6)
+cIAP1,2
MOMPMOMP: mitochondrial outer membrane permeabilisation
Vaux & Silke Nat Rev MCB 2005
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Only XIAP can directly block caspases-3 and -9
Riedl and Shi, Nat Rev MCB 2004
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Selective Interactions Between BH3-Only and Bcl-2-Like Proteins
Bim, Bid, Puma ABT-737
Obatoclax (Nguyen et al PNAS 2007)
(Oltersdorf et al Nature 2005)
Chen et al Mol Cell 2005(modified)
A1
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The Bcl-2 Family – Still Many Open Questions
9
BH3-only
Bcl-2-like
Bax/Bak
Strasser, Nat Rev Imm 2005
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BOK: A BAX/BAK-Like Protein?
10
BOK: BCL-2 related ovarian killer (Hsu et al. PNAS 1997)
Ke F. et al., CDD 2012
BOK is widely expressed
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Beroukhim et al., Nature, 2010
BOK is Deleted in Human Cancers with high Frequency
11
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BOK IS NOT A FUNCTIONAL BAX/BAK HOMOLOGUE
Echeverry et al., in revision
• BOK induces intrinsic apoptosis upstream of BAX/BAK
• BOK localises predominantly to non-mitochondrial sites:– Golgi, ER/nuclear outer membrane– nuclear compartment
• Bok-/- cells present with aberrant ER stress response (part. BFA)
+4-OHT (h):
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Death Receptor-Induced Killing and Crosstalk to Intrinsic (mitochondrial) Apoptotic Pathway
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APOPTOSIS IS ONLY ONE OF SEVERAL POSSIBLE OUTCOMES IN DR SIGNALING
NFkB
Necroptosis
Proliferation
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FADD/C8 (?)
RIP3 RIP1
FLIP
Apoptosis
FADD/TRADD
procaspase-8
TNFa
cIAP1/2
cell survival
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TNF-R1: Not Meant to Kill
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NFkB
Necroptosis
cytokines
RIP3 RIP1
Apoptosis
FADD/TRADD
procaspase-8
cIAP1/2
anti-apoptotic genes=> cell survival
TNF-R1
TNFa
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• Bacterial LPS -> TNFa (Macrophages, Neutrophils, NK T)
• Response via soluble, circulating TNFa TNF-R1 (Pfeffer et al 1993, Rothe et al 1993, Grivennikov et al 2005)
• Sensitisation by D-(+)-galactosamine (GalN)
LPS plus Galactosamine Injection Model of TNF-R1-Mediated Fulminant Hepatitis
Maeda S et al. Immunity 2003
Kaufmann et al. (2009)
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tBidCaspase-8
Cyt.cApaf1/ Caspase-9
Effector Caspases
X?Bax/Bak
Bid
Bcl-2-like
TYPE II
Caspase-8
Effector Caspases
TYPE I
Bid
Hepatocytes are Type II Cells
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The BH3-Only Protein BIM Is Rapidly Phosphorylated in LPS/GalN-Induced Hepatitis
*
Kaufmann et al. Immunity (2009)
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Both BID and BIM are Involved in LPS/GalN-Induced Hepatitis
Kaufmann et al. Immunity (2009)
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BIM is Activated by JNK Mediated Phosphorylation
A
*
B+/- D-JNKI1 (30 mg/kg, i.p.)
Kaufmann et al. Immunity (2009)
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JNK
Bim
Both BID and BIM can Mediate a Crosstalk from Death Receptors to Mitochondria
Corazza et al. JCI (2006)JNK mediated BIM-activationdownstream of TRAIL
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Fas/CD95/Apo-1
• FasL mainly expressed on activated T cells and natural killer cells. • Critical role in the control of the immune system• Fas or FasL-mutant mice develop lymphadenopathy and SLE (systemic
lupus erythematosus)-like disease and are predisposed to lymphoma development
• Many ALPS patients have heterozygous inherited mutations in the Fas gene. (Fisher et al. Cell 1995, Rieux-Laucat et al. Science 1995)
• Only the membrane bound form of FasL is inducing cell death (O’Reilly et al. Nature 2009)
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tBid
Fas
FasL
Caspase-8
Cyt.cApaf1/ Caspase-9
Effector Caspases
X?Bax/Bak
Bid
Bcl-2-like
TYPE II
Caspase-8
Effector Caspases
Fas
FasLTYPE I
Bid
Type I or Type II Fas-Induced Apoptotic Pathway
?
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X
Many Cancer Cells Display a Mandatory Crosstalk
X
?
MOMPX
Bcl-2
XMitochondrium
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Aim: Uncoupling of Death Receptor Pathway
Bcl-2
XMOMP
drugX
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Combination Therapy
Bcl-2
MOMP
ABT-737ABT-737
ABT-737drug X
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- Viral hepatitis- Alcoholic liver disease
- Autoimmune hepatitis- Graft-vs-host disease (GvHD)
- Endotoxin-induced liver failure
- Ischemia/reperfusion-induced liver damage
Importance of Apoptosis in Liver Pathology
-> -> Hepatocellular carcinoma(HCC)
Abnormal apoptosis in hepatocytes is cause or contributing factor in:
death receptors (hepatocytes)
death ligands (activated leukocytes)
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Murine Hepatocytes are Type II-Like Cells
Jo2 anti-Fas – ALT (200 min)
wt bid-/- lpr wt bid-/- lpr
PBS Jo2
Jo2aFas
wt
bid-/-
scale bar: 50 mm
+FasL (0.25 mg/kg)
FasL (crosslinked)
Kaufmann et al. Cell 2007Jost et al. Nature 2009 (modified)
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Lack of BID Blocks Fas-Induced Apoptosis in Type II but not in Type I Cells
Jost PJ et al., 2009 (modified)
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XIAP is Stabilised in Livers of FasL-Treated WT Mice
Jost PJ et al. (2009), modified
+ FasL (0.25 mg/kg)
p<0.05
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Jost PJ et al., 2009
Absence of XIAP Re-Sensitises Bid-Deficient Mice To FasL-Induced Hepatitis
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Absence of XIAP Converts Hepatocytes Into Type I Cells
DEVD-AMC Assay
Jost PJ et al., 2009
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Effects of IAP Antagonistic Drug (BV6) Phenocopies Genetic Loss of XIAP
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Kaufmann, Strasser & Jost, CDD 2011
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mast cell
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Neutrophils: - most frequent leukocyte in human blood- major role in innate immunity- end-differentiated, short-lived- apoptotic clearance of activated
neutrophils essential
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0 24 48 72 960
20
40
60
80
100
untreatedGM-CSF 1ng/mlG-CSF 10ng/mlQ-VD oph 20uM
C57BL/6 WTS
urvi
val (
%)
Time (h)
Primary Neutrophils Die By Classical Apoptosis When Cultured In Vitro
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0 24 48 72 960
20
40
60
80
100
wt untreatedbid-/- untreatedwt TNFabid-/- TNFa
0 24 48 72 960
20
40
60
80
100
wt TNFa
bid-/- TNFa
wt TNFa + Q-VD-oph
bid-/- TNFa + Q-VD-oph
TNFα 50 ng/ml
Q-VD oph 20 μM
Neutrophils die by Apoptosis in Response to High Doses of TNFa
Time (h)
Su
rviv
al %
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FasL Induced Cell Death is Delayed In Bid-/- Neutrophils
Geering et al. Blood 2011
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n>3
FasL Trigger Both Apoptosis and Necroptosis in Neutrophils
0 24 48 72 960
20
40
60
80
100
FasL
FasL + Q-VD-oph
0 24 48 72 960
20
40
60
80
100
FasL + Q-VD-oph
FasL + Q-VD-oph + Nec
0 24 48 72 960
20
40
60
80
100
FasL
FasL + Q-VD-oph
0 24 48 72 960
20
40
60
80
100
FasL + Q-VD-oph
FasL + Q-VD-oph + Nec
Su
rviv
al %
Su
rviv
al %
Su
rviv
al %
Su
rviv
al %
wt
bid-/-
bid-/-
wt
h
FasL 100 ng/ml, Q-VD oph 20 μM, Necrostatin-1 20uM
h
hh
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Loss of BID Aggravates Dextran Sodium Sulfate-Induced Colitis
d0 d1 d2 d3 d4 d5 d6 d7 d8
DSS in drinking water water
an
ima
l we
igh
t (%
)
0 1 2 3 4 5 6 7 885
90
95
100
105
wtbid-/-
* ** ******
***
*n.s.
n.s.
days
=> BID is anti-inflammatory
DSS colitis: -> dependent of neutrophils + macrophages
-> independent of adaptive immune system
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Proinflammatory role for BID?
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Ex Vivo Generation of Neutrophils Using Conditional Hoxb8
d0d5
43
Protocol based on Wang et al. Nature Methods 2006
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Roles of XIAP in Neutrophils
0 24 48 720
20
40
60
80
100
SCF-condHoxb neutrophils
wt TNF-a
XIAP-/- TNF-a
hours
Viab
ility
[%]
TN
Fa
(pg
/ml)
SCF-condHoxb8 neutrophils
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Non-apoptotic roles of XIAP
NOD2
MDP
NFkB
cytokines
XIAP
Damgaard et al. Mol Cell 2012
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IAPs Limit Inflammasome Activation In Macrophages
Vince J. et al. Immunity (2012)
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SUMMARY
• Several poorly characterised BCL-2 family members• Besides BID, BIM can mediate a crosstalk from DR to
mitochondria• XIAP is a crucial discriminator between type I and
type II Fas-induced apoptosis• FasL triggers mix of apoptosis and necroptosis in
neutrophils• Non-apoptotic roles of IAPs and DRs become
increasingly evident (important)
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ACKNOWLEDGMENTS• Philipp Jost (Munich DE)
• Mads Gyrd-Hansen (Kopenhagen, DK)
• Christoph Borner (Freiburg i.Brsg., DE)
• Georg Häcker (Freiburg i. Brsg., DE)
• Thomas Brunner (Konstanz, DE)
• Frank Essmann (Tübingen, DE)
• Julia Fernandez-Rodriguez (Gothenburg, SE)
• Kurt Ballmer (Villigen, CH)
University of Bern (CH)• Nohemy Echeverry• Ursina Gurzeler• Tatiana Rabachini• Daniel Bachmann• Simone Wicki• Nicole Tochtermann• Laetitia Roh
• Hans-Uwe Simon• Mario Tschan• Shida Yousefi• Clemens Dahinden
WEHI, Melbourne (AU)• Andreas Strasser• Francine Ke• Paul Ekert• John Silke • David Huang• Ueli Nachbur
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LUBAC: linear ubiquitin chain assembly complex
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50Andrea L 2009