Non-apoptotic functions of apoptosis-regulatory proteins

Abstract

During the past two decades, apoptotic cell death has been the subject of an intense wave of investigation, leading to the discovery of multiple gene products that govern both its induction and execution. In parallel, it has progressively become evident that most, if not all, proteins that had initially been discovered for their essential role in apoptosis also mediate a wide range of non-apoptotic functions. On the one hand, apoptotic regulators and executioners are involved in non-lethal physiological processes as diverse as cell cycle progression, differentiation, metabolism, autophagy and inflammation. On the other hand, pro-apoptotic proteins can control other modalities of programmed cell death, in particular regulated necrosis. In this review, we summarize the unconventional roles of the apoptotic core machinery from a functional perspective and discuss their pathophysiological implications.

Figure 1. Pro-inflammatory functions of caspase-1.

Several stress conditions can trigger the assembly of the inflammasome, a multiprotein platform for the activation of caspase-1 consisting of specific PRRs such as NLRP1 and NLRP3 and the adaptor protein ASC. Active caspase-1 catalyses the proteolytic processing of pro-IL-1β and pro-IL-18 followed by the secretion of mature IL-1β and IL-18 into the extracellular milieu. BCL-2 and BCL-XL inhibit IL-1β and IL-18 secretion by binding to NLRP1. ASC, apoptosis-associated speck-like protein containing a CARD; BCL, B-cell lymphoma; IL, interleukin; NLRP, NLR family, pyrin domain containing; PRR, pattern recognition receptor.

Figure 2. Cell cycle control by apoptotic regulators.

Several pro- and anti-apoptotic proteins have been shown to influence cell cycle progression. This can occur in a rather generalized fashion (as exemplified by the caspase-3-dependent release of prostaglandin E2 by dying cells) or involve specific cell cycle phases (as exemplified by the fact that cells overexpressing DIABLO are selectively arrested at the G₁–S boundary). Moreover, apoptotic regulators can control the cell cycle under physiological circumstances (as suggested by the fact that ENDOG-deficient cells accumulate at the G₂–M transition in the absence of any other stimulus) or in response to stress (as exemplified by caspase-2 and APAF-1, the depletion of which affects the cell cycle arrest induced by DNA damage). APAF-1, apoptotic peptidase activating factor 1; BAX, BCL-2-associated X protein; BCL, B-cell lymphoma; BID, BH3 interacting domain death agonist; CDK2, cyclin-dependent kinase 2; CDKN1, cyclin-dependent kinase inhibitor 1; DIABLO, direct IAP binding protein with low pI; ENDOG, endonuclease G; FADD, FAS-associated death domain protein; LATS1, large tumour suppressor, homologue 1.

Figure 3. Metabolic roles of BCL-X_L, cytochrome c and AIF.

Both cytochrome c and AIF are essential for the function of the respiratory chain, and thus for mitochondrial ATP generation through the F₁F_o ATPase. In particular, cytochrome c mediates the transport of electrons between complex III and complex IV, while mammalian AIF is critical for the structural stability of complex I. BCL-X_L binds to the F₁F_o ATPase, thereby stimulating its enzymatic activity. AIF, apoptosis-inducing factor; BCL, B-cell lymphoma; IM, inner mitochondrial membrane; OM, outer mitochondrial membrane.

Figure 4. Anti-necrotic functions of caspase-8 and FADD.

In response to TNFα, the intracellular tails of TNFR1 trimers drive the assembly of a supramolecular complex including, among other factors, TRADD, TRAFs, cIAPs and RIPK1. Upon ubiquitination, RIPK1 can stimulate the canonical pathway of activation of the anti-apoptotic and pro-inflammatory transcription factor NF-κB. Alternatively, deubiquitinated RIPK1 can interact with RIPK3 and trigger necroptosis. The pro-apoptotic proteins FADD and caspase-8, the latter by cleaving RIPK1 and RIPK3, tonically inhibit this pro-necrotic signalling cascade. cIAP, cellular inhibitor of apoptosis protein; FADD, FAS-associated death domain protein; NF-κB, nuclear factor-κB; RIPK; receptor-interacting protein kinase; TNFα, tumour necrosis factor α; TNFR1, TNFα receptor 1; TRADD, TNFR1-associated death domain protein; TRAF, TNFR-associated factor.

Lorenzo Galluzzi, Guido Kroemer, Christina Trojel-Hansen & Oliver Kepp