Key Points
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The ubiquitin system regulates key components in apoptotic signalling cascades and thus maintains proper homeostasis of multicellular organisms.
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Ubiquitin ligases (E3s) are the enzymes that specify which substrates are ubiquitylated, whereas deubiquitinases (DUBs) remove ubiquitin moieties. Improper regulation of either E3s or DUBs may result in improper execution of apoptosis and thereby contribute to various diseases.
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By promoting ubiquitylation and proteasomal degradation of caspases and second mitochondrial activator of caspases (SMAC), X chromosome-linked IAP (XIAP) and cellular inhibitor of apoptosis (c-IAP) proteins can inhibit apoptosis initiated by extrinsic or intrinsic stimuli. In addition, through the regulation of nuclear factor-κB (NF-κB) and tumour necrosis factor-α (TNFα)-stimulated signalling pathways, the E3 ligase activity of c-IAP proteins can determine cell fate in various tissues and cellular settings.
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Ubiquitylation and deubiquitylation of receptor-interacting protein 1 (RIP1) critically regulates the switch from anti-apoptotic to pro-apoptotic outcome by allowing the formation of kinase-activating signalling complexes or activation of caspases.
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Pharmacologic inhibitors of ubiquitin ligases and DUBs that promote therapeutic benefit by modulating critical regulators of apoptosis are in pre-clinical development or in clinical trials. The best examples are IAP antagonists, inhibitors of ubiquitin-specific protease 7 (USP7) deubiquitinase activity and compounds that block the p53–MDM2 interaction.
Abstract
The proper regulation of apoptosis is essential for the survival of multicellular organisms. Furthermore, excessive apoptosis can contribute to neurodegenerative diseases, anaemia and graft rejection, and diminished apoptosis can lead to autoimmune diseases and cancer. It has become clear that the post-translational modification of apoptotic proteins by ubiquitylation regulates key components in cell death signalling cascades. For example, ubiquitin E3 ligases, such as MDM2 (which ubiquitylates p53) and inhibitor of apoptosis (IAP) proteins, and deubiquitinases, such as A20 and ubiquitin-specific protease 9X (USP9X) (which regulate the ubiquitylation and degradation of receptor-interacting protein 1 (RIP1) and myeloid leukaemia cell differentiation 1 (MCL1), respectively), have important roles in apoptosis. Therapeutic agents that target apoptotic regulatory proteins, including those that are part of the ubiquitin–proteasome system, might afford clinical benefits.
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We thank researchers from Genentech Inc., South San Francisco, California, USA, for their helpful comments and critical reading of the manuscript.
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FURTHER INFORMATION
Glossary
- Thioester linkage
-
An ATP-dependent linkage formed between the carboxy-terminal group of ubiquitin and the Cys thiol group of E1 enzymes.
- Isopeptide linkage
-
An amide bond that forms between a side-chain carboxyl group and amino group and is not present on the main chain of a protein. In the case of ubiquitylation, isopeptide linkages form between the -nitrogen of Lys side chains and the C-terminus of the incoming ubiquitin, and constitute the basis of polyubiquitin chains.
- RING domain
-
A ubiquitin ligase domain that is defined by the presence of a catalytic zinc-finger-like module that chelates two zinc ions in a unique 'cross-brace' structure.
- HECT domain
-
Homologous to the E6AP (also known as UBE3A) carboxyl terminus, the HECT domain is a ubiquitin ligase domain that contains a catalytic Cys residue, allowing it to accept the charged ubiquitin from the E2 enzymes and transfer it directly to a substrate.
- BIR domain
-
(Baculovirus inhibitor of apoptosis (IAP) repeat domain). Coordinates zinc binding and is required for the anti-apoptotic activity of IAP proteins.
- WD40 domains
-
Protein domains that comprise multiple WD40 repeats that form a scaffold for protein-protein interactions. WD40 repeats are structural motifs of ∼40 amino acids that terminate in Trp (W) and Asp (D) residues.
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Vucic, D., Dixit, V. & Wertz, I. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12, 439–452 (2011). https://doi.org/10.1038/nrm3143
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DOI: https://doi.org/10.1038/nrm3143
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