¹Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent University, Ghent (Zwijnaarde), Belgium

Correspondence: P Vandenabeele, Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium. Tel: +32 9 33 13 760; Fax: +32 9 33 13 609; E-mail: peter.vandenabeele@dmbr.ugent.be

²Current address: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, U.S.A.

Received 21 July 2006; Revised 17 August 2006; Accepted 18 August 2006; Published online 20 October 2006.

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-B activation. Here, we discuss recent data indicating that non-apoptotic 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-B 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.