control of signaling-mediated clearance of apoptotic cells by the
TRANSCRIPT
Alex CioffiLiterature Seminar
August 8th 2015
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
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
Poon, I.K.H.; Lucas, C.D.; Rossi, A.G.; Ravichandran, K.S. Nat. Rev. Immun. 2014, 14, 166.
Cell clearance after apoptosis
The guardian of the genome
Aylon, Y.; Oren, M. Cell 2007, 130, 597.
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
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
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
DD1α plays essential roles in apoptotic cell
engulfment
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Impaired clearance of apoptotic cells in DD1α-
null mice
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Impaired clearance of apoptotic cells in DD1α-
null mice
DD1α expression on macrophages is required
for apoptotic cell engulfment
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Intercellular hemophilic DD1α interaction
between apoptotic cells and phagocytes
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Intercellular hemophilic DD1α interaction between apoptotic cells and phagocytes
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
DD1α-deficient mice develop autoimmune and
severe inflammatory disorder
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
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Inhibitory role of DD1α in T cell activation
Yoon, K.W. et al. Science 2015, 349, 1261669-1.
Conclusion