Index Caspase CARD/DED/BIR Bcl-2  DD TNF/TNFR Kinases ILs Viral Lipid Engulf TF RING Toll Other Apop Other NFkB Alphabet

Caspase Regulators  and Other CARD/DED/Pyrin-N/BIR proteins
 
Effector Domain Subgroup Protein Name
Apoptosis
NFkB activation
 Binding Partners
3D
 Structure
KO
 gene Locus transription regulators upstream regulators Expression
 cleaved by caspase memo
death  domain-like
a-helix rich homophilic domain
 CARD



















 Nod type






 Ced-4 [C.elegans]
Ced-3 activation
   Ced-3, Ced-9, FEM-1
CARD/NOD
1
 1 3




Apaf-1 [human  (S, L, XL), mouse, rat, dog(partial), zebrafish]
casp9 activation
(-)
 casp9, cyt-c, Bcl-xL, caspase 8, Aven CARD(1,2)
Apaf-1/Casp9, EM		 CARD/NOD/WDR
L
 1 12q22-q23 p53 irradiation, LPS,  OX-CA, Ma, insulin, RARb ubiquitous
 1
DARK, Dapaf-1, Hac1(D. m), Dapaf-1S
promote
DRONC, DrICE, DCP2(DREDD)
CARD/NOD/WDR
1
 1 2 53E1-53F1
irradiation


Nod1, CARD4 (human, mouse, rat)
promote
induce
 RICK, Nod1, CLAN, Caspase-1, Caspase-9, TRIP6, Hsp70, Hsp90, LPS prep (iE-DAP, DAP)
CARD/NOD/LRRs
L, (-),  asthma,  atopic eczema, hay fever, CD, CHD(-)
 1,2 7p14-p15
c-Myc, IL1, IL6, IRF1, IFNg, LPS, Hp, Se, Sp, methamphetamine ubiquitous

Nod2, CARD15 (human, mouse, rat)
promote
induce
 RICK, CLAN, caspase-1, Erbin, NIK, GRIM19, (MDP)
CARDx2/NOD/LRRs L, Crohn, PPROM, Blau, allergy, colon cancer/(-), breast cancer, psoriasis/(-), sarcoidosis, sepsis, UC, (-), (KI?)
 1 16q12 NF-kB TNFa, IL1, IL6, IFNg, LPS, Hp,  Se, Sp
 APCs

CIITA, MHC2TA (human (B, DC),mouse, rat)
inhibit
(-)
 CBP, CREB, NF-Y, RFX5, RFXAP, HDAC1, RFXANK, PCAF, TFIIB(TAFII32), CIITA, NCoA1, CRM1
(CARD)/AD/NLS/PST/NOD/NLS/LRR
BLS2, L
 1 16p13
IRF1, IRF2, IRF4, Stat1, STAT3, USF1, NF1, PU.1, E47, TEF2-like, CREB, Myc, AP1, AML2, BRG1, Rb
 IFNg, TGFb, IL1b, IL4, IL5, IL10, IL13, TSH, GM-CSF, NO, Chlamydia, Tg, dsDNA, CpG, dsRNA, MCMV, Mt19K, Nef, CsA, TNFa(-), PKCa, TncRNA, methylation, 5-azaC, cannabinoid APCs, B
targets, MHCII transactivator, AT?, Ub
Ipaf, CARD12, CLAN (human, mouse partial)
induce
induce
 Asc, Caspase 1, Bcl10, Nod1, Nod2, Nac
CARD/NOD/LRRs 1
 1 2p22-1p22
TNFa, UV, p53


DEFCAP, CARD7, NALP1, NAC [human L/a, g, d]
induce
Caspase-1, -2, -9, Apaf-1, CLAN, Asc
PD
 PyrN/NOD/LRRs/PyrN/CARD
1 17p12-13

T, B, NK, myeloid, APCs

Adaptor type



 RAIDD, CRADD [human, mouse]
induce/(-)
RIP, PIDD, Casp2, Ced-3
CARD, DD
 CARD/DD
L
 1,2 12q21.33-q23.1
PMA, LPS, HCMV, UVB, irrad., Nef, insulin, KCl
 ubiquitous
IBD-related?
RICK, RIP2, CARDIAK, RIPK2 [human, mouse, zebrafish]
promote/inhibit
induce
 CLARP, c-IAP1, TRAF-1,-5,-6, TRAF2,  casp1, Nod1, Nod2, IKKg, COP, Bcl10, p75NTR, TRIP6, TLRs
KD/IM/CARD
L
 1,2 8q21
LPS, Sa, Se, isochemia, camptothecin, TRIF ubiquitous

Bcl10, CIPER, CARMEN, mE10, CLAP, c-E10 [human, mouse, rat]
promote
induce
 CIPER, E10, DR4, TNFR1, TRADD, a-actinin,TRAF2, cIAP1, MALT1, CLAN, RICK, Pellino2, IKKs, UBC13, CARD9, -10,-11,-14, TFIIB
CARD(E10)/MBD/ST-rich
L
 1,2 1p22 Pax6 cantharidin ubiquitous, (highest level in preB, B, T, NK, epithelium, myeloid)

Ub
ASC, TMS1  [human, mouse, rat, bovine, zebrafish]
enhance/inhibit
induce
 Asc, Caspase-1, -8, Caspy, NALP1, Ipaf, Pyrin, IKKs, Cryopyrin, Bax
PD
 Pyrin-N/CARD L
 1 16p11.2-p12.1 p53 IL1, TNFa, IFNa, IFNg, LPS, FasL APCs

CARD6 [human, mouse, rat]
(-)
inhibit
 Nod1, RICK, CARD6, NAC, TUCAN
CARD/unknown
1 5p12

B, T, monocytes

Decoy type


 TUCAN, CARDIAL, CARD8, NDPP1 [human]
inhibit/ induce
inhibit
 Caspase-1, -9, ICEBERG, COP, Cryopyrin, IKKg, DRAL
NAC-like/CARD
1 19q13.33
camptothecin T, B, NK, APCs

ARC, myp-nop30 [ human, rat 24.6 kDa E/P-rich (L, S)]
inhibit/(-)/induce
caspase-2,- 8, Ced-3, SRp30c, CK2
CARD/EP-rich
1 16q21-q23
serum withdrawal, hypoxia, CK2 heart, s.muscle, sm. muscle

ICEBERG [human]
inhibit
 caspase-1
CARD
1 11q21-q22
LPS,TNFa ubiquitous

INCA [human]
(-)
 Casp1, COP, ICEBERG
CARD

11q22.3
IFNg, TNFa


COP/pseudo-ICE[human]
(-)
induce
 caspase-1, RICK
CARD
1 11q22




Bimp type


 CARD9 [human, (1, 2, 3), rat, carp]
induce
 Bcl10
CARD/coiled-coil
1 9q34.3

APCs

Bimp1,CARD10, Carma3 [human, mouse]
induce
 Bcl10, IKKg
CARD/coiled-coil/MAGUK
1 22q13.1

ubiquitous, (highest in liver, lung, epithelial)
PKC
Bimp2, CARD14, Carma2 [human, mouse]
induce
 Bcl10
CARD/coiled-coil/MAGUK
1 17q25

erythroid

Bimp3, CARD11, Carma1 [human, mouse]
induce
 Bcl10, MALT1, IKKg, PDK1
CARD/coiled-coil/MAGUK
L
 1 7p22

B, T, NK, mDC

DED




 Adaptor type

 human CLARP(1,2), Casper, I-FLICE, cFLIP(L,S), FLAME-1(a,b,g,d), CASH, MRIT, usurpin(a, b, g), CFLAR, mouse (a,b), rat(S), pig (L, S), zebrafish
induce/inhibit
induce/ inhibit
 casp8, FADD, casp3,TRAF1/2, Bcl-xL, RICK, RIP, Raf-1, DAXX, p38, p105, Hbx, MLH1, MBD4
DED/DED/Casp-like
1
 1 2q33 p53, E2F1, NF-kB, AP1, CREB, FOXO3a, HNF4a, c-Myc
 BCR, CD28, PMA, TNF/(-), CD40, IL4, IL10, IL12, IL18, TGFb, Notch3, SCF, LPS, KF1B, MDP, dsRNA, Bm, Ld, Lm, Mt, Tg, HSV, EV71, glucose, heat shock , Akt, PI3K/PTEN, LPA, S1P, keratin 8, Erk/MAPK, Ub, SLT, E1A, PPARg ligand, bile acid, depsipeptide, PS-341, doxorubicin, ceramide, 5FU, camptothecin, ribavirin blood cells (highest in lymphocytes)
 L Ub
FADD, MORT1(human, mouse, rat), dFADD(fly, Ag)
induce/inhibit, (IRF3)
induce
 Fas, DRs,TRADD, casp8, E6, ABCA1, LARP, Dcp2, Imd, DAP3
DEDF25G, 
DED F25Y, 
DD		 DED/DD
L, Dm
 L 11q13.3
LPS, heat shock, UV, ActD ubiquitous (highest in preB)

PEA15 (human, mouse, hamster)
inhibit
 (integrin act.) phospholipase Ds, ERKs, Omi
DED
 DED
1
 1 1q21.1
Myc, A-Myb, B-Myb, UV, Akt, cisplatin, doxorubicin, mitomycin C brain, spinal chord
glucose transport
DEDD-type
 DEDD/DEFT/KE05/FLDED-1/dedpro1(human, mouse, rat, zebrafish)
induce?
FADD, Casp8, Casp10
DED/(DB-like?)
1
 1 1q21

ubiquitous
Ub
DEDD2, FLAME3(human)
induce
inhibit
 Clarp, Casp8, Casp10, DEDD, hTFIIIC102
DED
1 19q13.31

blood cells

incorrectly reported proteins FLASH(mouse), SCC-S2/NDED(human), BAR(human), HIP1/HIPPI(human) CARP(human) Also see FLASH for NF-kB regulators, BAR for E3, HELICARD & RIG-I for Toll regulators
 no DED/CARD homology







Pyrin/PAAD/DAPIN















 Nod type, (NALPs) cryopyrin, Pypaf1, C1orf7, AII-AVP, AGTAVPRL, NALP3 ([human L, S, i], mouse, rat)
enhance
enhance/inhibit
 Asc, CARD8
Pyrin-N/NOD/LRR FCU, MWS, NOMID, CINCA
 1 1q43-q44
TNFa, LPS, LTA, dsRNA, MeDNA APCs

(19)
 Pypaf7, Pan6, Monarch-1, Nalp12, Cat19.3, RNO2 (human, mouse, rat)
enhance

Pyrin-N/NOD/LRR
1 19q13.42

APCs

  Nod12, Pypaf3, Nalp7,  Cat19.4 (human)
inhibit, (-)

Pyrin-N/NOD/LRR
1 19q13.42
LPS, IL1b


(11)
 NBS1, NALP2, Pypaf2, Pan1 (human)
 inhibit, (-)
 Asc
Pyrin-N/NOD/LRR
1 19q13.42




  Nod6, Nalp9, Cat19.1 (human)



Pyrin-N/NOD/LRR
1 19q13.42

ubiquitous (highest  in placenta)

  Nod17, Pypaf6, Nalp11, Cat19.6 (human)
(-)

Pyrin-N/NOD/LRR
1 19q13.42

ubiquitous

(18)
 Pan2 , NALP4, Pypaf4, Cat19.5 (human)
(-),inhibit
 IKK1
Pyrin-N/NOD/LRR
1 19q13.42
MeDNA ubiquitous at lowest level

  Nod14, Nalp13, Cat19.7 (human)



Pyrin-N/NOD/LRR
1 19q13.42




  Nod16, Nalp8, Pan4, Cat19.2 (human)



Pyrin-N/NOD/LRR
1 19q13.42




(15)
 Mater, Pypaf8, Nalp5, Cat19.8 (human, mouse)



Pyrin-N/NOD/LRR
1
 1 19q13.42

erythroid

(2)
 Pypaf5, Pan3, Nalp6, Cat11.4 (human)
enhance

Pyrin-N/NOD/LRR
1 11p15.5

ubiquitous (highest in intestine)

  Nod5, Nalp14, Cat11.2 (human)



Pyrin-N/NOD/LRR
1 11p15.4

ubiquitous

  Nod8, Nalp10, Pan5, Cat11.1, PYNOD (human) inhibit
 inhibit

Pyrin-N/NOD
1 11p15.4

ubiquitous


Nod27 (human)



Pyrin-N/NOD/LRR
1 16q13

B, T, NK, APCs

Decoy type PYC1, POP1, Asc2, ASCI, ASCL (human) induce
inhibit
 Asc
Pyrin-N
1 16p11.2
TNFa, LPS, IL4, IFNa, IFNg, IL10, TGFb, colchicine, AgII ubiquitous

Pyrin Pyrin, Marenostrin (human, mouse)
inhibit/enhance
inhibit/enhance
 Asc, P/M-IP1, 14-3-3
Pyrin-N/B box(ZF)/SPRY MEFV, BD, 1, (-)
 1 16p13.3 NF-kB,C/EBPb IFNg, IFNa, LPS, TNF/(-), IL4,  ubiquitous

IFI200 type see IFI20x proteins



Pyrin-N/IFI200s







non-homophilic type
 BIR










 E3 type



 API1, cIAP-1, HIAP-2, MIHB, BIRC2 (human, mouse, rat), zebrafish, catfish
inhibit
TRAF1/2, caspase 3/7, RICK, LTbR, SMAC, HtrA2, DKFZP586F1524
BIR
 BIRx3/CARD/RING
1
 1 11q22-23 NFkB, p53, HNF4a LPS(-), dsRNA, CpG, flagellin, LTA, Ct, Hp, Lm, Ye, DV, TNFa/(-), TRAIL, Fas, CD30,  IL5, shear stress, ER stress, p21WAF1, PI3K, FAK, Smac, camptothecin B, T, NK, APCs & their precursors
 L Ub ligase
API2, cIAP-2,, HIAP-1, MIHC, ITA, BIRC3 (human, mouse, rat, chick)
inhibit
induce
  TRAF1/2,caspase 3/7, SMAC, HtrA2
BIRx3/CARD/RING
1
 1 11q22-23 NFkB, p53 TNFa/(-), IL1, TRAIL, Fas, TL1, CD30,  LPS(-), MDP, LTA, BLP, flagellin, Ct, Hp, Lm, Ng, St, Ye, HHV8, EV71, CD40, CD30, CD8/28, G-CSF, SCF, cAMP, PGE2, PMA, Epo, irrad,  UVA, hypoxia, CsA, bryostatin 1, PKCd, MKK7, SIRT1, IL10, DEX, FAK, Smac, camptothecin; c-IAP1
 B
Ub ligase
XIAP, MIAP3, hILP, MIHA, API3, BIRC4 (human, (mouse, rat, bovine, zebrafish
inhibit
induce
 ZAP-1, caspase 3/7, TAB1, BMPR-IA, HtrA2, GSPT1, TGFbR1, NRAGE, MURR1, Casp9, SMAC, survivin, TAK1, XIAP
BIRs, w/Diablo, w/casp3, casp7
 BIRx3/RING
L
 1,2,3 Xq25 NF-kB
 Fas, APRIL, M-CSF, FGF2,  PMA, LPS(-), heat shock, Epo, sIL6R, calpain, Akt, FAK, TCDD, CY61 ubiquitous 1/(-) Ub ligase
ILP-2, BIRC8 (human, gorilla, chimp)
inhibit
caspase-9
BIRx3/RING

19q13.3-q13.4

testis

livin, ML-IAP, KIAP, BIRC7 (human,L)
inhibit
caspase-9
BIR/RING
1
 1 20q13.33

ubiquitous

Nod type NIAP, BIRC1, Lgn1 (human), mouse NIAP-1, 2, rs3, 4, 5, rs6, 6, 7
inhibit
hippocalcin, TAK1, caspase-9
BIRx3/NOD/LRRs
1
 1,2,3 5q12.2-q13.3
CD3/CD28, LPS, MeDNA, isochemia, gonadotropin, UV, TCDD APCs
Legionella resistance

PsiNAIP (human)  


BIR/NOD/LRRs

5q11.2-q13.1




Other



 survivin, tiap, BIRC5 [human, mouse, rat, pig, dog, chicken, Xl(1,2), zebrafish (1, 2), Deterin (D.m.), Ag]
inhibit
Cdk4/p16(INK4a), AuroraB, Smac, HBXIP, Hsp90, XIAP
L
 BIR
L
 1 15q21 Sp1, STAT3, p53 IFNb,  TNFa, IL8, IL11,  thrombopoietin, Flt3L, SCF, insulin, NO, CDC2, PML, cisplatin, Rapamycin, doxorubicin., UVA, HIV Vpr, taxol, AdV, FKHR, estrogen ubiquitous (highest in erythroid, bone marrow, preB, embryo, oocyte)
cytokinesis
Drosophila[DIAP1, DIAP2(DIHA)], Tn-IAP1(butterfly), IAP(fall armyworm, silk worm)
inhibit
reaper, hid, grim, Doom, Skl, DCP-1, DrICE, /w DRONC, Jafrac2
Diap1 BIR, w/Grim, Hid, Dronc
 BIRx2-3/RING
1
 1, 2 diap1, 2
Rpr,Hid, Grm, Hippo

Ub ligase, casp
C.elegans BIRPs [C50B8.2, T27F2.3]
no effect


BIR
1




cytokinesis
BIR1,S.pombe[C2C6.16], S.c.[YJR089w]



BIRx2/ATP
1
 1




cytokinesis
BRUCE, apollon (human, mouse), CG6303(D.m.), Ag
inhibit
Nrdp1, Smac, HtrA2
BIR/UBC
1
 1 2p22-p21
Hoxd10
1
 Ub E2/E3

Other Nods

 Nodtype Nod3 (human)



?/NOD/LRR
1 16p13.3





Nod9 (human, mouse)



?/NOD/LRR
1 11q23.3





 

-On-line review-

Review of

Inohara N, Chamaillard M, McDonald C, Nunez G. NOD-LRR Proteins: Role in Host-Microbial Interactions and Inflammatory Disease. Annu Rev Biochem. 2005
Inohara N, Nunez G.  "NODS: Intracellar proteins involved in inflammation and apoptosis".  Nat Rev Immunol 3, 371-382
Inohara N, Ogura Y, Nunez G. "Nods: a family of cytosolic proteins that regulate the host response to pathogens." Curr Opin Microbiol. 2002 5, 76-80.
Inohara N, Nunez G. "The NOD: a signaling module that regulates apoptosis and host defense against pathogens". Oncogene 2001 Oct 1;20(44):6473-81
Nunez, G., Benedict, M.A., Hu, Y., Inohara, N. "Caspases: The proteases of the apoptotic pathway."  Oncogene 1998 Dec 24;17(25):3237-45

Apaf-1/caspase regulators by Green (Cell 1998)
Apoptosomes by Adams JM, Cory S. (Curr Opin Cell Biol  2002)
Caspase Activation by Shi Y(Cell 2002)
Ced-4 by Vaux (Cell 1997)
Ced-4/Apaf-1 by Hengartner (Science 1998)
Cytokines & IBD by Papadakis1 & Targan (Annu. Rev. Med. 2000)
IAPs by Martin (Cell 2002), Goyal (Cell 2001), Reed (Genes Dev 1999), Miller (Trends Cell Biol 1999)
Review by Dixit & Strasser (2000), Nagata (2000)

Annual reviews

 

Comparison of Mutants Between Caspase and Caspase RegulatorsUnder Construction

 
 
Apaf-1
Caspase-9
FADD
Caspase-8
Caspase-3
Caspase-2
 Caspase-1
Caspase-11
 Caspase-12
Bcl-xL
Bcl-w
Bcl-2(1,2,3)
 Mcl1 A1
Bax(1,2,3)
 Bax/Bak Bak
Bid
 Bim Puma Noxa Bad Hrk
Tissue development
Brain
Ab, n(5%)
R
 n
n
 R
N
n
n
E
 
 

r/ab
ab/r
 (ab)
N


N
 n?
 
eye
Ab
 n
 
n
 R
 
n
n
 
 
 

 
n
n



n
 
limb
ab
 N
 
n
 n
 
n
 
 
 

 
ab
n



n
 
heart & muscle
(n)
 
Ab
ab
 n
 
N
n
 
 
 

 

N


N
 n
 
kidney
(n) 
 
 
 
 n
 
N
 
 
Ab

 N
N
 N
N
 CNT

N
 n
 
hematopoiesis
N
N
R
Ab
 N
 
N
n
 E(T cell)
 
E
  
r
R
N
Ab


n
 
placenta developement,
blood vessels
 
 
N
 
 n
 
n
 
 
 

 






n
 
oogenesis
 (n)
 
 
 
 
r
 ab
 
 
 E

 





N
 n
 
spermatogenesis
 Ab
 
 
 
 
 
 
 
E
 

 Ab

N


N
 n
 
hair follicles
 
 
 
 
 
 
n
 
 
Ab

 


CNT


n

implantation











Ab










B survival










ab





cnt

N

T survival
  

 
N




ab





cnt

N

negative selection
n






















TCR/CD3/CD28 activation, ionomycin, PMA
N

N













R
R
N

BCR

















R

ab

mast cell / neutrophil activation












R









granulocyte survival
  








N
N

N


Ab




myeloid suvival










ab




R
cnt




cranial bone formation 
Ab
Ab












N







External Vaginal Introitis













N
Ab
 N





Irr. & Chemo etc
gamma-irradiation
R 
R
 
 
 
 N
 
 
 
E

N


(r)

n
 
UV-irradiation
R
R
 
N 
r
 
 
 
 
 

 N
R
 N


N

 
adriamycin
R
R
N
 
 
 
 
 
 
 

 
  
R

N


5-fluorouracil










E

N

R




 
C6-ceramide
 
 
 
N
 N
 
 
 
 
 

 







 
Staurosporine
R 
 
 
N
 N
N
 
 
 
 

 



R
N
 
Etoposide
R
 
 
 
 
N
 
 
 
 

 N
R
N


N
N
 
Cysplatin
R
 
 
 
 
 
 
 
 
 

 




N

 
Dexamethasone
 
R
 
 
 N
N
 
N
 
 
 E

 


R
R
N
 
Doxoriubicin
 
 
 
 
 
r
 
 
 
 

 








p53 overexpression













r








AraC
















N




withdrawal 
suvival factor stavation
  
 
 
N
 
 N
 
 
 
 

r
R
 
R
 N
(r)
 r
TNF family response
Fas
N/r
N
R
R
 N, r
 N
r
N
 
 
 

N 
N/r
N
delay
N

(r)
 
TNFalpha/CHX
 N
N
R
R
 
 
r
 
 
 

 

delay


N
 
DR3
 
 
R
 
 
 
 
 
 
 

 








TRAIL/DR4/DR5

R










r
R
r
N




 
anti-CD120a
 
 
 
R
 
 
 
 
 
 

 







 
ov-ex. TRADD
 
 
r
 
 
 
 
 
 
 

 







 
ov-ex.FADD
 
 
N
 
 
 
 
 
 
 

 







 
ov-ex.caspase-8
 
 
N
 
 
 
 
 
 
 

 







 
JNK activation
 
 
 
N
 
 
 
 
 
 

 







 
NFkB activation
 
 
 
N
 
 
 
 
 
 

 








viral response

Ab
Ab/(-)


















Other
Cyt-c release
N
 
 
 
 
 
 
 
 
 

 







 
Loss of membrane potential
R
r
 
 
 
 
 
 
 
 

 







 
E1A
 
 
N
 
 
 
 
 
 
 

r?




r?

 
c-myc
r 
r
N
 
 
 
 
 
 
 

 
R
N





 
CD3/CD28
 
R
 
 
 N
 
 
 
 
 

 







 
granzyme B
 
 
 
 
 
r
r
 
 
 

 








ER-stress
n






r





R







beta-amyloid







r














ischemia



r
r

















axotomy





















r

kainate-induced neuronal CD













r








IL-1b secretion





Ab















(R, r), Reduce apoptosis; (E, r) Enhance apoptosis; (N, n), normal; (cnt), counter the phenotype of mice lacking another gene.
Induction of apoptosis and NF-kB activation by Apaf-1/Nod1 family members and DD proteins (Inohara et al., 2000). The more recent study suggested that IKKgamma binds to the site in C-terminal regulatory region of IKKbeta which is located after the HLH motif.

Images

Activation of Caspase-8 and Caspase-9
Activation of NF-kB by Nod1/RICK and TNFa signaling pathways
Proximity-Activation Model for Caspase-8(A) and Caspase-9(B)
Links for Crohn's disease
Endoscopic pics of CD from various regions (oral cavity to anus) (GASTEROLAB)
X-ray pics from ileal CD (Gastrointestinal X-ray Atlas)
microscopic pics of CD.


Copyright by Naohiro Inohara, Department of Pathology, University of of Michigan Medical School
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