Caspases are a family of cysteine proteases expressed as inactive zymogens in virtually all animal cells. These enzymes play a central role in most cell death pathways leading to apoptosis but growing evidences implicate caspases also in nonapoptotic functions. Several of these enzymes, activated in molecular platforms referred to as inflammasomes, play a role in innate immune response by processing some of the cytokines involved in inflammatory response. Caspases are requested for terminal differentiation of specific cell types, whether this differentiation process leads to enucleation or not. These enzymes play also a role in T and B lymphocyte proliferation and, in some circumstances, appear to be cytoprotective rather than cytotoxic. These pleiotropic functions implicate caspases in the control of life and death but the fine regulation of their dual effect remains poorly understood. The nonapoptotic functions of caspases implicate that cells can restrict the proteolytic activity of these enzymes to selected substrates. Deregulation of the pathways in which caspases exert these nonapoptotic functions is suspected to play a role in the pathophysiology of several human diseases.

Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-B activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-B activity through RIP1 cleavage. IntroductionA family of cysteine proteases, known as caspases, plays a central role in many forms of apoptosis. 1 Two main pathways of caspase activation leading to apoptosis have been described. The intrinsic pathway involves the disruption of the outer mitochondrial membrane barrier function, thus permitting the release of proapoptotic molecules from the mitochondria to the cytosol. These molecules include cytochrome c that, in the presence of ATP, trigger oligomerization of a platform protein named apoptosis-activating factor 1 (Apaf-1). This protein recruits and activates caspase-9 in the apoptosome. In turn, caspase-9 cleaves and activates downstream effector enzymes such as caspase-3. The extrinsic pathway starts at the level of plasma membrane by engagement of death receptors such as Fas/CD95, tumor necrosis factor receptor 1 (TNF-R1), and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. In the presence of their respective ligand, death receptors recruit the adaptor molecule Fas-associated death domain (FADD) protein, which, in turn, recruits and activates an initiator enzyme, usually caspase-8, in the death-inducing signaling complex (DISC). Caspase-8 either directly activates the caspase cascade or connects the extrinsic to the intrinsic pathway through cleavage of the sentinel BH3-only protein Bid. 1,2 Additional pathways of caspase activation involve either dependence receptors in the absence of their ligand, 3 or interaction of Apaf-1-like molecules with the adaptor moleculeASC, 4 or endoplasmic reticulum stress that activates caspase-12 in mice and caspase-4 in humans. 5 Although in most cases caspase activation engages cells to die, recent evidence indicates nonapoptotic functions of these enzymes. For example, caspase-8 was involved in lymphocyte activation, 6 which might account for the combined T-and B-cell, and natural killer (NK)-cell immunodeficiency in patients with mutated caspase-8. 7 The enzymatic activity of caspase-8 is also required for fetal liver hematopoietic stem cell proliferation. 8 Sig...

IntroductionThe inhibitors of apoptosis proteins (IAPs) have been initially defined as natural cellular inhibitors of cell death. These proteins were identified in baculoviral genome as regulators of host-cell viability during virus infection, 1 and cellular orthologues were subsequently described in yeast, nematodes, drosophila, and mammals. The human genome encodes at least 8 IAPs (X-linked IAP [XIAP], cellular IAP1 [c-IAP1], c-IAP2, melanoma IAP [ML-IAP], neuronal apoptosis inhibitory protein [NAIP], survivin, IAP-like protein 2 [ILP-2], Apollon). 2 All of these proteins have in common the presence of 1 to 3 copies of a baculovirus IAP repeat (BIR) domain. 1 These domains are essential for the antiapoptotic properties of the IAPs, which have been attributed to the direct binding and inhibition of caspases. XIAP binds the small subunit of caspase-9 through its BIR3 domain 3 and masks the active site of caspase-3 and -7 through a distinct segment, which is immediately amino-terminal to its BIR2 domain. 4,5 c-IAP1 and c-IAP2 bind caspase-3 and -7 but their inhibitory effect on caspases is 2-to 3-log lower than that of XIAP. 6 Some of the BIR-containing proteins do not have clear links with apoptosis and several members of the family have demonstrated distinct functions including cell cycle regulation, 7 protein degradation, 8 and caspase-independent signal transduction. [9][10][11][12] In addition to the BIR domains, several IAPs, including XIAP, c-IAP1, and c-IAP2, contain a highly conserved carboxy-terminal RING finger domain that confers them an enzyme 3 (E3) function in the protein ubiquitylation process. Several proteins specifically targeted for ubiquitylation by IAPs have been identified. At least in vitro, XIAP and c-IAP2 direct the ubiquitylation of caspase-3 and caspase-7, 13,14 whereas c-IAP1 and c-IAP2 mediate ubiquitylation of second mitochondria-derived activator of caspase (Smac)/ DIABLO, an antagonist of IAPs. 15 c-IAP1 and c-IAP2 are also components of the type 2 tumor necrosis factor (TNF) receptor complex through interaction with the signaling intermediates TNF receptor-associated factor 1 (TRAF1) and TRAF2. 9 c-IAP1 could induce the ubiquitylation of TRAF2 and participated in the TNF-␣-mediated proteasomal degradation of TRAF2, 16 and c-IAP2 has been involved in the TNF-␣ signaling leading to nuclear factor-B (NF-B) activation. 17 The expression and activity of IAPs are regulated at several levels. The transcription factor NF-B enhances the expression of c-IAP1, c-IAP2, and XIAP, which may contribute to the prosurvival effect exerted in many situations by this transcription factor. 18,19 XIAP translation can be enhanced through the use of an internal ribosomal entry site in the 5Ј-untranslated region of its messenger RNA. 20 Another level of regulation of IAP functions is the modulation of their subcellular location. Such a regulation has been described for XIAP whose interaction with the protein XIAP-associated factor 1 (XAF1) induces its sequestration in the nucleus and suppresses its casp...