Intrinsic and Extrinsic Apoptosis


I’m going to summarize the finer points of intrinsic and extrinsic apoptosis. As always, if you have comments, concerns, or corrections, please comment below!

Intrinsic and extrinsic apoptosis differ in how they are initiated and how they go about activating executioner caspases (caspase 3 and 6 are the major players). Intrinsic is initiated by lots of things including ER stress, decreased growth factors, and genetic damage, among others. Meanwhile, extrinsic is initiated by binding of Fas-FasL forming a Fas associated death domain (FADD) on the cell undergoing apoptosis.

INTRINSIC

Image result for intrinsic apoptosis
https://www.easybiologyclass.com/intrinsic-pathway-of-apoptosis-apoptosis-molecular-mechanism-part-1/

Intrinsic apoptosis starts with some mechanism OTHER than Fas-FasL binding, things like DNA damage, ER stress, decreased growth factors, etc. Sensors of apoptosis, the BH3 proteins (Bim, Bid, PUMA, NOXA, etc) are upregulated telling the cell to undergo apoptosis. If the cell has undergone DNA damage, the BH3 protein PUMA (p53 upregulated modulator of apoptosis) may have increased expression levels due to increased p53 levels.

Once the cell has committed (so to speak) to undergo intrinsic apoptosis, the mitochondrial membrane proteins that are anti-apoptotic are replaced with pro-apoptotic proteins (Bcl-2/Bcl-x/Mcl-1 –> Bax/Bak). The way I remember that is the proteins without an “a” are anti-apoptotic, the proteins with an “a” are pro-apoptotic. Bax and Bak allow the mitochondria to leak proteins, including cytochrome C. Cytochrome C binds to APAF-1 (apoptosis-activating factor-1) which also binds to caspase-9, forming the apoptosome. This activates caspase-9 allowing to activation of the executioner caspases and DNAse activity downstream.

There are inhibitors of apoptosis (IAPs- including IAP, IAP1, cIAP2, XIAP, I’m sure there’s more) that are active within the cytosol. When Bak/Bax create pores in the mitochrondrial membrane, Smac/Diablo is released along with cytochrome C. Smac/Diablo function to block IAPs (inhibiting the inhibitors = pro-apoptotic).

EXTRINSIC

Image result for extrinsic pathway of apoptosis
https://www.creative-diagnostics.com/extrinsic-apoptosis-pathway.htm

Extrinsic apoptosis is initiated by the binding of Fas (CD95) to FasL (but binding to TRAIL and the TNFα receptor TNFR1 can also induce the extrinsic pathway of apoptosis). When any of those receptors are activated they create a FADD (or TRADD)- Fas-associated death domain, where three receptors are brought close together. A FADD/TRADD will bring together pro-caspase 8 molecules close together, which is autocatalytic for cleavage into active caspase 8 (the way I remember that caspase 8 is with extrinsic apoptosis is that eight and extrinsic both start with “e”). Caspase 8 then activates executioner caspases 3 and 6 which leads to apoptosis.

The protein FLIP (aka cFLIP, CFLAR) binds to, but does not activate, pro-caspase 8, making it an anti-apoptotic protein.

There can be cross over between the two pathways. When Bid (BH3 protein) is activated, in Fas signaling induced apoptosis (extrinsic) it can activate the incorporation of Bax/Bak into the mitochondrial membrane and subsequent cytochrome c release (leading to intrinsic apoptosis).

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