ARTS-1, HtrA2, BRE, tBid, FLASH, c-Jun, TNF-R1, Caspase-9, Caspase-2, c-IAP1, c-IAP2, FADD, jBid, Apaf-1, JNK (MAPK8-10), XIAP, Caspase-3, c-FLIP (S), IKK-gamma, Bid, RIPK1, Smac/Diablo, Caspase-6, Bid = jBid, NF-kB, MEK4 (MAP2K4), MEKK1 (MAP3K1), Caspase-8, Cytochrome c, IKK (cat), Caspase-7, I-kB, TRADD, MKK7 (MAP2K7), Bid = tBid, RAIDD, TNF-alpha, Bax, SODD, Bcl-2, TRAF2, GCK (MAP4K2), Caspase-10
Role TNF-alpha in apoptosis
The tumor necrosis factor ( TNF-alpha ) is a potent cytokine produced by many cell types, including macrophages, monocytes, lymphocytes, keratinocytes and fibroblasts, in response to inflammation, infection, injury and other environmental challenges. TNF-alpha elicits a particularly broad spectrum of organismal and cellular responses of cell proliferation, differentiation and apoptosis .
TNF-alpha exerts its effects through two distinct receptors, TNFR1 and TNFR2 . Binding of the inherently trimeric TNF-alpha to TNFR1 induces receptor trimerization and recruitment of TNFR1-associated death domain protein ( TRADD), which serves as a platform to recruit at least three additional mediators: receptor-interacting protein 1 ( RIP1 ), Fas-associated death domain protein ( FADD ), TNF-receptor-associated factor 2 ( TRAF2 ). The adaptor protein transmits an activating signal from the activated receptor TNFR1 to some signaling cascades - caspase cascade with subsequent apoptosis, NF-kB activating cascade and JNK cascade .
Recruiting of FADD and RIPK by TRADD results in activation of the caspase cascade followed by apoptosis. Adaptor proteins FADD and RAIDD participate in activation of initiator caspases caspase-2, -8, and -10 by the activated receptor TNFR1. Initiator caspases cleave and activate effector caspases caspases-3, -6 and -7. Effector caspases are responsible for the proteolytic cleavage of a broad spectrum of cellular targets, which ultimately leads to cell death , .
Recruiting of TRAF2 and RIPK by TRADD lead to an activation of survival transcription factor NF-kB. RIPK and TRAF2 recruit IKK-gamma and IKK alpha/beta subunits of IKK (inhibitor of nuclear factor kappa B kinase ) complex respectively , . It was shown that RIPK1 and TRAF2 both are necessary for IKK activation .
The NF-kB pathway might intersect with the apoptotic pathway via induction of antiapoptotic protein BCL-2 and cellular inhibitors of apoptosis ( c-IAP1, c-IAP1, XIAP ), which function as specific caspase inhibitors , . Moreover, c-IAP1 and TRAF2 form a complex which direct inhibites of caspase-8 cleavage and activation under TNF-alpha signaling .
TNF-alpha also activates the JNK signaling cascade and results in an activation of the transcription factor AP-1 and subsequent increase proliferation. TRAF2 interact with and activate MEKK1 activating JNK cascade .
Involvement of the JNK cascade in TNF-alpha -mediated apoptosis is controversial.
It was shown that TNF-alpha -induced activation of JNK results in the cleavage of apoptotic protein Bid at the 25 position amino acid. A specific Bid cleavage product ( jBid ) approximately 21 kDa in size subsequently translocates in the mitochondria and is capable to release Smac/DIABLO (mitochondrial Smac protein) from mitochondria without affecting the cytochrome c localisation . In the cytoplasm, Smac/DIABLO binds XIAP, c-IAP1, c-IAP2, and abolishes the inhibitory action on caspases . Additionally, Smac/DIABLO acts on and disrupts the TRAF2 - c-IAP1 complex and abolish its inhibition on caspase-8 .
Some regulators of TNF-alpha -signaling were detected. Silencer of death domain ( SODD ) binds TNFR1 and prevents self-aggregation and spontaneous downstream signaling at ligand absent.
SODD dissociates from TNFR1 upon receptor ligation .
BRE (brain and reproductive organ-expressed protein) inhibits both TNF-alpha- induced activation of NF-kB and apoptotic pathways .
ARTS-1 (aminopeptidase regulator of TNFR1 shedding) increases TNFR1 shedding and decreases membrane-associated TNFR1, thereby decreases the TNF-alpha signal .