in this video of cell signaling we will be discussing about necroptosis it is a signaling pathway which leads to cell execution through the tumor necrosis factor then necroptosis is programmable form of necrosis just like we have apoptosis which is gas space dependent programmed cell death in the same way we have necrotosis which is gas-based independent programmed cell death both the pathways are mediated through tnfr1 that's tumor necrospector receptor one to start the necroplasty signaling pathway we see we have the cell membrane and in the cell membrane we have the tnf receptors in the form of
monomoles distributed over the plasma membrane as shown in the diagram in the structure of tnf r1 it has got that domain to its intracellular side and this that domain mediates downstream signaling but this domain remains inhibited by the action of another protein called sodd that silencer of that domain now let's initiate the signaling first of all the tnf alpha molecules which are the signaling molecules in this pathway are present outside of the cell as shown in the diagram here in this animation tnf alpha molecules comes in and binds the tna preceptors on the plasma membrane
and binding of dnf alpha induces trimerization of tnf receptor as shown in the diagram once the trimerization is completed the sodd leaves the dead domain and from here the downstream signaling starts first of all that domain of tnf r1 recruits trade protein and rip cabin protein then this tread protein in turn recruits trap to protein and this tractor protein is one of the important proteins here because it allows for the engagement of ubiquitin ligase which is ciap cellular inhibitor of apoptosis protein so here we saw the binding of ciap towards the receptor complex then from
here many different pathways emerge first of all iap promotes ubiquitination of its own molecules and rip cabin molecules and once the ubiquitination is completed furthermore the lubac is recruited which induces extensor ubiquitination of rip carbon iap trapped to tread molecules also now we have the ubiquinated complex it leads to activation of tag 1 type 2 type 3 complex which in turn activates nemo protein that finally leads to nfkb or nf capability pathway activation and this nf kappa b pathway activates c flip s molecules the detailer and kappa b pathway is already discussed in the video
linked in the description now we stop from here because we need the c plip as molecule later in the negro process pathway now getting back to the tread trap rip complex here the complex is ubiquinated and to get into necrotosis pathway first we need to de-ubiquinate the proteins and it's done by cyld molecule so from this process we get the dubiquinated rip k1 protein which further recruits f add as shown in the diagram in the next step the fadtt rip k1 complex recruits caspase-8 molecule it can lead to apoptosis from here if caspase remains as
such but to prevent the caspase cascade we need to deactivate or inhibit the caspase-8 molecule and it's done by the c-flip s molecule from the nfkb pathway we got the c-clip as molecule this c-clip has forms dimer with gas base 8 and it renders caspase-8 inactive thereby inhibiting apoptosis but it must be noted that if c flip s does not inactivate the caspase-8 the higher levels of rip k3 molecule renders caspase-8 and a2 which we are going to see later in this video so we see here the phosphorylated rip k1 recruits rip k3 and this
rip k3 is auto transphosphorylated which then also inactivates caspase-8 proceeding further the activated rip k1 and rip k3 complex phosphorylates and activates mlkl monomers and induces oligomerization of mlkl monomers the mlkl oligomer is then translocated into the plasma membrane as shown in the diagram where it forms october 4. this pore will allow for the entry of damps and rose which eventually leads to cell death so this is how necroptosis is accomplished also remember during the process of necrotosis the tnf tnfr1 crosstalks with riboflavin kinase which then interacts with many different proteins like p22fox and nox
proteins to get the functional nadph oxidase which then eventually generates ros that also adds to the necro of tosses so this concludes the necroptosis signaling pathway i hope you liked the video if you liked it give it a thumbs up do consider supporting my work on patreon and also make sure to subscribe this channel thanks
