control of signaling-mediated clearance of apoptotic cells by the

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