Introduction

Apoptosis is a form of programmed cell death characterized by cell shrinkage, nuclear condensation, DNA fragmentation, membrane blebbing, and preserved cytoplasm membrane integrity till late stages [1]. Apoptosis is a regulated process conducted by caspase activation. Caspases are cysteine aspartases initially present in zymogen forms and get cleaved and activated upon certain apoptotic stimulation. The initiator caspases (Caspase-2,-8,-9,-10) are the upstream components of the caspase-cascade. Their structurally unique feature is the large pro domain that allows them to be recruited in multimeric signaling complexes, which promotes their dimerization and mutual cleavage. Caspase-8 and 10 are recruited into the so called DISC (death inducing signaling complex) after death receptor (e.g. Fas, TNFa) stimulation, while Caspase-9 activation takes place in the apoptosome protein complex. Formation of this complex is dependent on the release of mitochondrial pro-apoptotic proteins [2]. The activation of initiator caspases leads to direct cleavage of executioner caspases (caspase-3, 6 and 7) which then directly results in cleavage of caspase substrates calling forth the biochemical and morphological features of apoptosis.

 

Necrosis is characterized by cytoplasm swelling and early loss of cytoplasm membrane integrity. For decades, necrotic cell death had been exclusively attributed to accidental events. In the last decade, it became clear that cell death with necrotic features can be also considered as a regulated cell death modality in certain conditions [3]. This so called “necroptotic” pathway is mediated by specific regulator molecules as for instance: RIP1 (receptor (TNFRSF)-interacting serine-threonine kinase) and a recently discovered effector molecule: MLKL (mixed-lineage kinase-like protein) [5].

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Literature:

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(1) Wyllie AH. Apoptosis: cell death in tissue regulation. J Pathol. 1987; 153(4): 313-6

(2) Mace PD, Riedl SJ. Molecular cell death platforms and assemblies. Curr Opin Cell Biol. 2010; 22(6): 828–836

(3) Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014; 15(2): 135-147

(4) Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunol. 2000; 1(6): 489–495

(5) Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012; 148(1-2): 213–227

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