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Review
. 2009 Dec;21(6):878-84.
doi: 10.1016/j.ceb.2009.09.005. Epub 2009 Oct 21.

Regulation of cell death by the ubiquitin-proteasome system

Maya Bader  1 , Hermann Steller
Affiliations
Review

Regulation of cell death by the ubiquitin-proteasome system

Maya Bader et al. Curr Opin Cell Biol. 2009 Dec.

Abstract

The regulation of apoptosis (programmed cell death) has been the subject of a vast body of research because of its implications in normal development, tissue homeostasis and a wide range of diseases. The ubiquitin-proteasome system (UPS) plays a prominent role in the control of apoptosis by targeting key cell death proteins, including caspases, the central executioners of apoptosis. Here we summarize the major findings on the function of the UPS in both pro- and anti-apoptotic regulation.

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Figures

Fig. 1
Fig. 1. Role of Ubiquitin in the regulation of apoptosis
Ubiquitination plays opposing roles at different stages during the life-death decision in a cell. In cells that live, IAP-mediarted ubiquitination serves to inhibit unwanted caspase activity. IAP-dependant ubiquitination of caspases leads to inhibition of apoptosis through both proteasomal degradation and a non-degradative pathway. In addition, it can also be used to eliminate caspase activators, like apoptosome subunits [42]. Upon induction of apoptosis, IAP-RING function promotes self-conjugation and UPS-mediated degradation of IAP-proteins, thereby removing the “brakes on death” and facilitating the execution of apoptosis [29] [17] [25] [30]. Additionally, non-degradative ubiquitination can also directly activate caspases, by mediating self-cleavage through the induction of specific protein-protein interactions [36]. Besides IAPS, other E3’s, such as cullin-based E3 ligases, have also been shown to regulate caspase activation, as in sperm differentiation [57].
Fig. 2
Fig. 2
(A)Domain structure of RING-containing IAPs IAP family members are defined by containing at least one BIR domain, which mediates their interaction with caspases. In addition, the IAPs listed here also harbor a RING domain, enabling them to direct ubiquitination of substrate proteins. The three best studied mammalian IAPs (cIAP1, cIAP2, and XIAP) are shown here. cIAP1 and cIAP2 contain a Casapse Recruitment Domain (CARD). In Drosophila, DIAP1 is strictly required to prevent unwanted caspase activation and apoptosis in somatic cells. DIAP2 has a domain arrangement very similar to mammalian IAPs; it is important for regulating the innate immune response [65,66] and also inhibits the effector caspase Drice [67]. Bruce/Apollon is a giant BIR protein that also contains a Ubiquitin Conjugating (UBC) domain [68]. In mammals, Bruce was shown to inhibit apoptosis by binding and mediating the ubiquitination of Smac and caspase-9 [69,70], while in Drosophila it suppress death induced by RHG proteins [71], and might have a role in caspase activation during sperm differentiation [57]. (B) Cullin-based E3 ligases Cullins are scaffolding proteins that mediate the physical interaction between different subunits, like BTB and Fbox proteins, which are responsible for substrate recognition and RING domain containing proteins, necessary for E2 ligase recruitment. Cullins are known to interact with several distinct E2 ligase and numerous substrate recognition proteins, and this combinatorial arragement of proteins allows cullins to mediate both general and specific biological events (reviewed in [72]).
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