S377 Chapter 14

Cells can die by different mechanisms. Regulated cell death can be of several types, including apoptosis, which involves the action of ❌, and autophagic cell death, in which ❌ are involved. Other forms of death have been described. ❌ cell death is an unregulated response to severe physiological insults.

Dying cells can be identified not only by their appearance under the EM, but also by histochemical and biochemical methods that demonstrate ❌, membrane ❌ and ❌ activation.

❌, or programmed cell death, involves ❌ and signalling ❌ that are evolutionarily ❌ between animals from C. elegans to humans.
In mammals, many ❌ of these proteins have been identified, and apoptosis is under complex and tight ❌, which varies between different cell types.

❌ exist as ❌, the procaspases, which can be activated by two main routes; an ❌ pathway, which involves the activation of cell surface ❌, and ❌ routes, most of which involve the ❌.

Other organelles, in particular the ❌, also play a role in the regulation of cell death via ❌ pathways.

❌ are a family of ❌ that cleave substrates at aspartate residues.
There are two subfamilies of caspases, one involved predominantly in ❌ and the other in cytokine processing.
Inactive caspases (i.e. ❌) consist of a large and a small subunit and a ❌ of variable length.

Two types of caspase, ❌ caspases and effector ❌, are involved in cell death. Initiator caspases, when activated, go on to activate ❌ caspases, which in turn go on to cleave downstream ❌.

Initiator ❌ exist as monomers and possess a ❌ prodomain, which include either ❌ or DED domains. They are ❌, a process made possible by assembly into large multimolecular aggregates. This is called ❌ and involves interactions with homologous CARD or ❌ domains on other proteins.

❌ procaspases exist as ❌. They have a ❌ and are activated upon cleavage by ❌ caspases. Activation takes place by cleavage between the ❌, and removal of the ❌; activated effector caspases are ❌.

Certain activated caspases are inhibited by ❌, a family of proteins some of which are ❌ ligases. IAPs act by binding activated caspases, thereby inactivating them ❌, and also targeting them for ❌ at the ❌. (They may also act by a mechanism that involves their N-terminal amino acid.)
Caspases may be inhibited by ❌ peptides that have the same sequence of amino acids as that of the cleavage sites of their substrates.

The ❌ apoptotic pathway involves activation of ❌ by ligands that may be soluble or on the surface of other cells. The extrinsic pathway is involved in ❌ and is essential, among other things, for ❌ development and regulation of lymphocyte numbers following an ❌.
❌ (e.g. Fas) on the target cells ❌ upon binding of ligand (e.g. Fas ligand). The intracellular part of each death receptor includes a ❌ that is also present in ❌, which are hence recruited to the activated receptor to form a complex known as the ❌. The adaptors also possess a ❌, shared by some ❌ (e.g. procaspase 8). Thus initiator procaspases are recruited to the DISC and this proximity allows their ❌.
The activated initiator caspases may go on to directly cleave downstream ❌ (e.g. procaspase 3) or Bid, which stimulates the ❌ pathway.
Activation of the extrinsic pathway may be inhibited by ❌, or decoy adaptors/caspases, which lack ❌.