control of signaling-mediated clearance of apoptotic cells by the
TRANSCRIPT
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Alex CioffiLiterature Seminar
August 8th 2015
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Vucic, D.; Dixit, V.M.; Wertz, I.E. Nat. Rev. Mol. Cell. Biol. 2011, 12, 439.
ApoptosisIntrinsic
NOXA, proapoptotic gene
BAD, BCL-2 antagonist of cell
death
tBIM, truncated BCL-2-interacting
mediator of cell death
PUMA, p53 unregulated modulator
of apoptosis
BID, BH3-interacting domain death
agonist
BCL-2, B-cell lymphoma
MCL1, myeloid leukaemia cell
differentiation 1
BAK, BH antagonist or killer
USP9X, ubiquitin-specific protease
9X
FBW7, F-box- and WD repeat-
containing 7
MULE, MCL1 ubiquitin ligase E3
SMAC, second mitochondrial
activator of caspases
IAP, inhibitors of apoptosis
proteins
ML-IAP, melanoma IAP
X-IAP, X chromosome-linked IAP
Ub, ubiquitin
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Vucic, D.; Dixit, V.M.; Wertz, I.E. Nat. Rev. Mol. Cell. Biol. 2011, 12, 439.
ExtrinsicCD95, Death ligand
APO2, Death ligand
DR, death receptor
TNF, Tumor necrosis factor
FADD, FAS-associated DEATH
domain protein
FLIP, FLICE-inhibitory protein
RIP1, receptor-interacting protein 1
TNFR1, TNF receptor 1
TRADD, TNFR1-associated DEATH
domain protein
TRAF2, TNFR-associated factor 2
CYLD, deubiquitinase enchance
cell death
ITCH, E3 ubiquitin ligase
IAP, inhibitors of apoptosis
proteins
c-IAP, cellular IAP
Ub, ubiquitin
Apoptosis
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Poon, I.K.H.; Lucas, C.D.; Rossi, A.G.; Ravichandran, K.S. Nat. Rev. Immun. 2014, 14, 166.
Cell clearance after apoptosis
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The guardian of the genome
Aylon, Y.; Oren, M. Cell 2007, 130, 597.
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Identification of DD1α as a p53 target gene
Camptothecin (CPT) –
quinolone alkaloid, inhibits
DNA topoisomerase I, causes
apoptosis
Nutlin-3 – inhibits the
interaction of mdm2
(negative regulator of p53)
and p53, stabilizes p53,
antiproliferative effect in
cells with functional p53 but
not with mutant p53
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DD1α is widely expressed and has similarities
to T-cell immunoglobulins (TIM)
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Lk, leukocyte
Lu, lung
Pl, placenta
SI, small intestine
Li, liver
Ki, kidney
Sp, spleen
Tm, thymus
Co, colon
Sm, skeletal muscle
He, heart
Br, brain
identical conserved consensus
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
DD1α plays essential roles in apoptotic cell
engulfment
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Impaired clearance of apoptotic cells in DD1α-
null mice
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Impaired clearance of apoptotic cells in DD1α-
null mice
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DD1α expression on macrophages is required
for apoptotic cell engulfment
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Intercellular hemophilic DD1α interaction
between apoptotic cells and phagocytes
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Intercellular hemophilic DD1α interaction between apoptotic cells and phagocytes
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
DD1α-deficient mice develop autoimmune and
severe inflammatory disorder
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
DD1α-deficient mice develop autoimmune and
severe inflammatory disorderAb against IgG PAS staining Low Mag EM High Mag EM
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Inhibitory role of DD1α in T cell activation
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Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Conclusion