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Deadly encounter: ubiquitin meets apoptosis

Key Points

Summary

  • The first reports that linked apoptosis with changes in ubiquitylation and proteasome composition and activities emerged from studies of intersegmental muscle programmed cell death in the hawkmoth Manduca sexta. Proteasome-inhibitor-based studies further corroborated the proposed link between the ubiquitin/proteasome system and apoptotic pathways.

  • By transactivating various apoptogenic substrates, but also through transcriptionally independent activities, p53 can activate the two important apoptotic pathways in cells. The function of p53 is substantially controlled through ubiquitylation by Mdm2, a RING-finger-dependent ubiquitin protein ligase for p53.

  • In addition to p53, many cell-cycle regulatory proteins, such as cyclins and CDK inhibitors, affect apoptotic pathways. Modulation of proteasomal proteolysis of these regulatory proteins often affects the execution of apoptosis.

  • NF-κB directs the transcription of several survival genes, although, under some circumstances, it can also promote apoptosis. The ubiquitin/proteasome system effectively governs NF-κB activation by aiding the post-translational processing of the NF-κB precursors and by controlling its nuclear localization.

  • The delicate balance between pro- and anti-apoptotic Bcl-2 family members within a cell helps determine the susceptibility of a cell to a death signal. Various Bcl-2 family members have been identified as substrates of the proteasome, and inhibition of their degradation has been found to affect apoptosis.

  • In response to apoptotic stimuli, the ubiquitin-ligase activity of IAPs (inhibitors of apoptosis) can lead to their auto-ubiquitylation and degradation, which allows cells to commit to apoptosis. Moreover, IAPs are also instrumental in modulating the amount of caspases through ubiquitylation leading to proteolysis, thereby irreversibly shutting down specific cell-death pathways.

  • Seeing through the multiple links between the ubiquitin/proteasome system and the apoptotic machinery is expected to significantly extend the repertoire of possible treatments to diseases that are linked to dysregulated cell death.

Abstract

The ubiquitin/proteasome pathway is the main non-lysosomal route for intracellular protein degradation in eukaryotes. It is instrumental to various cellular processes, such as cell-cycle progression, transcription and antigen processing. Recent findings also substantiate a pivotal role of the ubiquitin/proteasome pathway in the regulation of apoptosis. Regulatory molecules that are involved in programmed cell death have been identified as substrates of the proteasome. Moreover, key regulators of apoptosis themselves seem to have an active part in the proteolytic inactivation of death executors.

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Figure 1: The ubiquitin pathway.
Figure 2: p53 and apoptosis.
Figure 3: The multiple roles of IAPs.
Figure 4: Control of NF-κB activity by the ubiquitin/proteasome system.

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Acknowledgements

Our apologies to those whose work could only be cited indirectly owing to space limitations. V.J. is supported by a Marie-Curie fellowship, S.J. by the Max Planck Society, Deutsche Forschungsgemeinschaft, European TMR network and Fonds der chemischen Industrie.

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DATABASES

Interpro

Bcl-2 homology domains

BIR motif

RING finger

UBC domain

 LocusLink

β-TrCP

AIF

Bax

Bcl-XL

BRUCE

cIAP1

cIAP2

Puma

TRAIL

 OMIM

Alzheimer's disease

Amyotrophic Lateral Sclerosis

Parkinson's disease

 Swiss-Prot

Apaf-1

Bad

BAG-1

Bak

Bcl-2

Bid

Bik

Bim

caspase-3

caspase-7

caspase-9

β-catenin

CD95

E6-AP

FADD

FAT10

FLICE

Gadd45β

Mdm2

Mdmx

p19ARF

p27Kip1

p53

p53AIP1

p100

p105

Perp

PTEN

Raf-1

Reaper

RelA

RelB

Scythe

Siah-1A

Skp2

Smac

TRAF1

TRAF2

TRAF6

Ubc13

Uev1A

VHL

XIAP

Glossary

APOPTOSIS

This is defined by stereotypical changes such as chromatin condensation, phosphatidylserine exposure, cytoplasmic shrinkage, membrane blebbing and the formation of apoptotic bodies. In its most classical form, apoptosis invariably involves caspase activation.

CASPASES

A family of cysteine proteases that can be grouped into initiator and effector caspases. Caspase activation requires their proteolytic cleavage to liberate subunits that reconstitute an active caspase heterodimer.

BCL-2 FAMILY

(B-cell lymphoma-2 family). These are proteins with a structural similarity to Bcl-2, the prototypical inhibitor of apoptosis. The Bcl-2 family comprises proteins that both block and enhance apoptosis.

IAPs

(Inhibitor of apoptosis proteins). These are intrinsic cellular inhibitors of apoptosis and are defined by the presence of BIR motifs.

26S PROTEASOME

A large barrel-shaped multisubunit protease complex that selectively degrades multiubiquitylated proteins. It contains a 20S subunit, which carries the catalytic activity, and two regulatory 19S subunits.

UBIQUITIN

A 76-amino-acid globular protein that is highly conserved throughout eukaryotes. Its covalent conjugation to other proteins is essential for the degradation of proteins.

E2 UBIQUITIN-CONJUGATING ENZYME

An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme (E1) and, usually together with a ubiquitin ligase (E3), transfers it to a substrate protein.

ISOPEPTIDE LINKAGE

Any amino bond formed between a carboxyl group of one amino acid and an amino group of another, in which either group occupies a position other than α.

SCF UBIQUITIN-LIGASE COMPLEX

A multisubunit E3 ubiquitin ligase, which is composed of Skp1, cullin-1 protein, F-box protein, and Rbx1/Roc-1 RING-finger protein. The F-box protein is the substrate-recruiting factor.

CBCVHL COMPLEX

An SCF-related complex of elongin B, elongin C, cullin-2 and the RING-finger protein Rbx1/Roc-1. The substrate-recognizing subunit pVHL binds to the elongin B/C complex through a motif known as the Socs box. It is believed that the von Hippel–Lindau cancer syndrome is a direct consequence of a loss of cellular CBCVHL-mediated ubiquitylation activity.

TUMOUR-NECROSIS FACTOR-α

(TNF-α) A prototypic member of a family of cytokines that interact with several receptors, among them receptors that are responsible for eliciting apoptosis.

PROTEASOME INHIBITORS

These are classified into four groups: lactacystin and β-lactone derivates, vinyl sulfones, peptide aldehydes and peptide boronates. The aldehyde and boronate inhibitors are reversible and more amenable to clinical use.

RING-FINGER PROTEINS

A family of proteins that are structurally defined by the presence of the zinc-binding RING-finger motif. The RING consensus sequence is: CX2CX(9–39)CX(1–3)HX(2–3)C/HX2CX(4–48)CX2C. The cysteines and histidines represent metal binding sites. The first, second, fifth and sixth of these bind one zinc ion and the third, fourth, seventh and eighth bind the second zinc ion. Many RING-finger proteins are ubiquitin ligases or subunits thereof.

TNF-RECEPTOR FAMILY

Members of this family function as trimers and multimers of trimers, and can trigger proliferation, survival, differentiation or death. A subfamily that comprises the death receptors Fas/CD95 and TNF-R1, as well as some other members of this family, contains a cytoplasmic region — the death domain — which is essential for inducing apoptosis.

E3 UBIQUITIN-LIGASE

An enzyme that covalently attaches ubiquitin to a substrate protein in conjunction with E1 and E2. E3s range from single polypeptide chains to large complexes in which substrate recognition and ubiquitin conjugation occur in distinct subunits. So far, every known E3 has either a homologous to E6AP carboxyl-terminus (HECT) domain, or a RING-finger domain.

JNK

The c-Jun amino-terminal kinase belongs to the group of mitogen-activated protein kinases (MAPKs) and is activated in mammalian cells by environmental stress, pro-inflammatory cytokines and mitogenic stimuli. JNK regulates the activities of many transcription factors, and is required for the regulation of inflammatory responses, cell proliferation and apoptosis.

CYCLINS

These function as positive regulatory subunits of cyclin-dependent kinases (CDKs). Cyclin–CDK complexes are usually activated at specific points during the cell cycle and have a specific set of substrates.

CDK INHIBITORS

These inhibit cell-cycle progression by regulating cyclin–CDK complexes. On the basis of their structural and functional properties, CDK inhibitors fall primarily into the INK4 group and the Cip/Kip family.

BIR MOTIF

A 70 amino-acid zinc-finger motif called the baculoviral inhibitor of apoptosis repeat. The number of BIR domains in a given IAP varies from one to three, but they are invariably present at the amino-terminus of the protein, and mediate the interaction with caspases.

UBIQUITIN-CONJUGATING DOMAIN

(UBC). The 16-kDa ubiquitin-conjugating domain of E2s harbours the active-site cysteine residue that is required for the formation of a thioester-linked E2-ubiquitin complex.

IκB-KINASE

(IKK). The 700–900-kDa IκB-kinase (IKK) complex includes the catalytic subunits IKKκ and IKKβ and the regulatory subunit IKKγ/NEMO. Both catalytic substrates are involved in the activation of NF-κB transcription factors, but they do so by distinct mechanisms and substrates. As shown by genetic studies, IKKβ is essential for inducible IκB phosphorylation and degradation.

TNF-RECEPTOR-ASSOCIATED FACTORS

(TRAFs). These are adaptor proteins for various cell-surface receptors. Most TRAFs encode a RING-finger motif at their amino-terminus; in the case of TRAF2 and TRAF5, the RING-finger is required for NF-κB activation.

TRAIL

(TNF-related apoptosis-inducing ligand). This induces apoptosis preferentially in transformed cells. In contrast to other death-inducing ligands, TRAIL is expressed in a wide range of tissues.

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Jesenberger, V., Jentsch, S. Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol 3, 112–121 (2002). https://doi.org/10.1038/nrm731

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