The Mechanism Of Death Receptor6-Induced Apoptosis

Cells undergo apoptosis via two major pathways, the death receptor pathway (theextrinsic pathway) and the mitochondrial pathway (the intrinsic pathway). Thecrosstalk between the death receptor pathway and the mitochondrial pathway ismediated by Bid, which is cleaved by caspase-8, and activated truncated Bid（tBid）formation. Upon triggering by distinct stimuli, each of these two pathways activatesan initiator caspase, caspase-8(the extrinsic pathway) and caspase-9(the intrinsicpathway), respectively, which in turn activates the executor caspase—caspase-3andfinally leads to apoptosis. Moreover，Both of these two pathways have involved in theneuronal cell degeneration found in Alzheimer disease. As reported，death receptor6(DR6) was shown to be implicated in the neurodegeneration observed in Alzheimerdisease.DR6(TNFRSF21) is a relatively new member of the death receptor family，and itwas shown that overexpression of DR6could induce apoptosis. A abundant DR6transcript was found in many tissues and cell lines，including neuronal cell.However，how the death signal mediated by DR6is transduced intracellularly is not known.Themechanism of DR6-induced apoptosis is the most important problem we need tofigure out. Which pathway is more crucial, either conventional death receptorpathway or mitochondrial pathway?In this study, we have determined the roles of caspase, mitochondrialpro-apoptotic protein cytochrome c, and Bcl-2family proteins in DR6-inducedapoptosis. Our results clearly demonstrated that Bax translocation is absolutelyrequired for DR6-induced apoptosis. On the other hand, inhibition or knockdown ofcaspase-8has no effect on DR6-induced apoptosis, and tBid formation is not requiredfor DR6-induced apoptosis since that knockdown of Bid could not blockDR6-induced apoptosis.As reported, two major apoptosis signaling pathways have been identified uponinduction of specific death receptors, type Ⅰ and type Ⅱ pathways. The level ofcaspase-8activation is considered to classify whether a cell is type Ⅰ or type Ⅱ, withtype Ⅱ cells less efficient at activating caspase-8following death receptor activation.In other words, the level of mitochondrial dependence is also thought todiscriminate type Ⅰ or Ⅱ. In my case, DR6-induced apoptosis is independent ofcaspase-8activation, which indicated that DR6-induced apoptosis is not via type Ⅰpathway. In addition, tBid formation is not required DR6-induced apoptosis, whichdemonstrated that DR6-induced apoptosis is not via type Ⅱ pathway. In a word, ourdata strongly suggest that DR6-induced apoptosis occurs via a new pathway that isdifferent from the type Ⅰ and type Ⅱ pathways through interacting with Bax.DR6is associated with neuronal cell degeneration, especially in Alzheimerdisease. The mechanism of DR6-induced apoptosis provides a theoretical basis to cureAlzheimer’s disease, but also find new targets for clinical trials and drug development.