Caspases in cell survival, proliferation and differentiation

Abstract

Caspases, a family of evolutionarily, conserved cysteinyl proteases, mediate both apoptosis and inflammation through aspartate-specific cleavage of a wide number of cellular substrates. Most substrates of apoptotic caspases have been conotated with cellular dismantling, while inflammatory caspases mediate the proteolytic activation of inflammatory cytokines. Through detailed functional analysis of conditional caspase-deficient mice or derived cells, caspase biology has been extended to cellular responses such as cell differentiation, proliferation and NF-jB activation. Here, we discuss recent data indicating that nonapoptotic functions of caspases involve proteolysis exerted by their catalytic domains as well as non-proteolytic functions exerted by their prodomains. Homotypic oligomerization motifs in the latter mediate the recruitment of adaptors and effectors that modulate NF-jB activation. The non-apoptotic functions of caspases suggest that they may become activated independently of -or without -inducing an apoptotic cascade. Moreover, the existence of non-catalytic caspase-like molecules such as human caspase-12, c-FLIP and CARD-only proteins further supports the non-proteolytic functions of caspases in the regulation of cell survival, proliferation, differentiation and inflammation. Cell Death and Differentiation (2007) 14, 44-55. doi:10.1038/sj.cdd.4402047; published online 20 October 2006 Caspases are an evolutionarily conserved family of aspartatespecific cystein-dependent proteases with central functions in apoptotic and inflammatory signalling pathways.1 Certain caspases have large prodomains that contain related homotypic oligomerization motifs such as the caspase recruitment domain (CARD,

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

“…Most caspase targets lose function when they are cleaved during apoptosis (Lamkanfi et al, 2007), although a small number of proteins acquire a new function after cleavage (Luthi and Martin, 2007). For example, cleavage of the BH3-only protein Bid by caspase-8 results in its acquisition of a proapoptotic function (Luo et al, 1998).…”

Coordinate regulation of autophagy and apoptosis in T cells by death effectors: FADD or foundation

“…5 cFLIP has been shown to modulate the induction of casp8 activity, either activating or inhibiting the proteolytic activity depending on the context of the signal. 6 The importance of DRs in maintaining immune homeostasis and preventing autoimmunity is strikingly clear in individuals lacking the DR CD95/Fas or its cognate ligand FasL. Mutations in the genes encoding either the receptor or the ligand lead to the development of severe lymphoadenopathy, splenomegaly and the production of autoantibodies, all due to the inability to eliminate activated lymphocytes.…”

Identification of a novel cyclin required for the intrinsic apoptosis pathway in lymphoid cells

“…The fact that cyclin O-Cdk1/2 complexes are involved in the activation of caspases opens the possibility that they may also regulate their activation during other non-apoptotic functions, such as tissue differentiation, cell proliferation or maturation of pro-inflammatory cytokines (reviewed in Lamkanfi et al 22,23 ).…”