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Ubiquitin and proteasomes

Sumo, ubiquitin's mysterious cousin

Nature Reviews Molecular Cell Biology volume 2, pages 202–210 (2001)Cite this article

Key Points

  • Covalent modification by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport and cell-cycle progression. But, in contrast to ubiquitylation, which generally targets proteins for degradation, sumoylation seems to either modulate the subcellular location of proteins or enhance their stability.

  • SUMO is highly conserved from yeast to humans. Whereas invertebrates have only a single SUMO gene, three members of the SUMO family have been described in vertebrates.

  • Like ubiquitin, all SUMO forms are initially made as inactive precursors. The processing reaction is catalysed by a group of cysteine proteases, termed ubiquitin-like protein-processing enzymes (ULPs) or SUMO-specific proteases (SUSPs).

  • In contrast to ubiquitin, SUMO conjugation does not seem to lead to the formation of SUMO?SUMO chains on the substrate.

  • Sumoylation is a dynamic, reversible process. De-sumoylation is catalysed by the ULP/SUSP proteases. In yeast, de-sumoylation is essential for viability.

  • SUMO has much fewer cellular substrates than ubiquitin, but several of these targets turn out to be important cellular regulators.

  • Sumoylation of the mammalian RanGAP1 protein, a component of the nuclear import machinery, is required for binding to Ran-binding protein 2 (RanBP2) at the nuclear pore complex. This indicates either that sumoylation targets RanGAP1 to the nuclear pore complex or that it stabilizes binding to RanBP2.

  • In higher eukaryotes, most other sumoylated proteins appear to be nuclear. Intriguingly, many are found in specific subnuclear protein complexes called promyelocytic leukaemia (PML) nuclear bodies.

  • Sumoylation of PML itself regulates the assembly/stability of these nuclear bodies. Upon sumoylation of PML nuclear-body-associated proteins, including the transcription factors Daxx and p53, are recruited to nuclear bodies. Intriguingly, p53 is itself a substrate for SUMO.

  • For the NF-κB inhibitor IκBα and the ubiquitin ligase Mdm2, it has been proposed that sumoylation and ubiquitylation are functionally linked. SUMO and ubiquitin seem to compete with each other for the same lysine residues within these proteins. SUMO could thus antagonize the function of ubiquitin and act as a stabilizer of IκBα/Mdm2.

Abstract

Covalent modification of cellular proteins by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport, signal transduction, stress response and cell-cycle progression. But, in contrast to ubiquitylation, sumoylation does not tag proteins for degradation, but seems to enhance their stability or modulate their subcellular compartmentalization.

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Figure 1: Sequence alignment of SUMO family members and ubiquitin.
Figure 2: Conjugation pathway of ubiquitin and the ubiquitin-like modifier SUMO.
Figure 3: Structure of the ULP-1?SMT3 complex.
Figure 4: Sumoylation of PML modulates Daxx-mediated transcriptional repression.
Figure 5: Reversible modification of proteins by SUMO and its consequences.

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Acknowledgements

We wish to thank C. D. Lima for the permission to include the structural data on ULP1-SMT3 in this review and we are indebted to many colleagues for sharing unpublished results. S. M. would like to express his special thanks to Anne Dejean for stimulating discussions, encouragement and continuous support during his stay in her laboratory.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, 82152, Germany

    Stefan Müller, Carsten Hoege, George Pyrowolakis & Stefan Jentsch

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  1. Stefan Müller
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  2. Carsten Hoege
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Supplementary information

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DATABASE LINKS

ubiquitin

RUB1

Apg8

Apg12

parkin

RAD23

DSK2

SMT3

SUMO-1

SUMO-2

SUMO-3

RanGAP1

AOS1

UBA2

UBA1

UBC9

UBC4

UBC7

ULP1

ULP2

SMT3IP1

SENP-1

SUSP-1

Ran

RanBP2

RNA1

semushi

PML

p53

Daxx

p73

Sp100

HP1

HIPK2

TEL

c-Jun

androgen receptor

Tramtrack 69

NF-κB

Mdm2

IκBα

TNF

Dorsal

Cactus

RING finger

CDC3

CDC11

SEP7

MIF2

RAD51

RAD52

DNA topisomerase I

DNA topoisomerase II

RecQ

BLM

CENP-C

FURTHER INFORMATION

Jentsch lab

ENCYCLOPEDIA OF LIFE SCIENCES

Nuclear?cytoplasmic transport

Ubiquitin pathway

Glossary

ISOPEPTIDE BOND

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

26S PROTEASOME

Large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

CYSTEINE PROTEASE

Protease that has a cysteine at the active site.

SUMO CONJUGATE PATTERN

Pattern of bands corresponding to sumoylated substrates detectable on an immunoblot with an anti-SUMO antibody.

EST

DNA sequence obtained by sequencing an end of a random complementary DNA clone from a cDNA library.

NUCLEAR PORE COMPLEX

Large multiprotein complex that forms a channel in the nuclear envelope of an eukaryotic cell, joining the inner and outer nuclear membranes and allowing transport of proteins to and from the nucleus.

BICOID

A segment polarity protein, discovered in Drosophila, that provides positional cues for the development of head and thoracic segments.

PML NUCLEAR BODIES

One type of nuclear speckles of unknown function that contains several proteins, including the promyelocytic leukaemia protein PML. PML nuclear bodies are also called PODs (PML oncogenic domains) or ND10 (nuclear dots 10).

RING-FINGER PROTEINS

A family of proteins 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.

HP1 FAMILY

(Heterochromatin protein 1 family). A family of chromosomal non-histone proteins primarily associated with heterochromatin. HP1 proteins have been implicated in gene regulation, DNA replication and nuclear architecture.

HMG1/2 FAMILY

(High-mobility group 1/2 ). Large protein family of small non-histone components of chromatin that function in higher-order chromatin structure.

HOMEODOMAIN TRANSCRIPTION FACTORS

Transcription factors with a 60-amino-acid DNA-binding domain comprised of three α-helices.

ETS

Proto-oncogene family related to v-ets, one of the oncogenes of the acutely transforming avian erythroblastosis virus E26.

POLYTENE CHROMOSOME

A giant chromosome formed by many replications of the DNA. The replicated DNA molecules tightly align side-by-side in parallel register, creating a non-mitotic chromosome that is visible by light microscopy.

IκBα

Inhibitory subunit of the NF-κB transcription factor, which is phosphorylated, ubiquitylated and degraded in response to activating stimuli.

MITOTIC SPINDLE

A highly dynamic bipolar array of microtubules that forms during mitosis or meiosis and serves to move the duplicated chromosomes apart.

SEPTINS

Highly conserved protein family first identified in yeast and more recently found in a wide range of animal cells. They are thought to function primarily in the control of cytokinesis, where they form a 10-nm filamentous ring that encircles the yeast bud neck.

HIGH-COPY SUPPRESSOR

Gene that suppresses a phenotype when expressed at high copy number.

CENTROMERE

Region of a chromosome that is attached to the spindle during nuclear division.

MINICHROMOSOME

An extrachromosomal plasmid DNA that contains a chromosomal origin of replication.

SYNAPTONEMAL COMPLEX

Structure that holds paired chromosomes together during prophase I of meiosis and that promotes genetic recombination.

WERNER SYNDROME

A rare autosomal recessive disorder, characterized by the early development of various age-related diseases. The gene responsible for Werner syndrome (WRN) encodes a DNA helicase homologous to Escherichia coli RecQ.

BLOOM SYNDROME

A rare cancer-predisposing autosomal recessive disorder characterized by genomic instability, immunodeficiency and small stature. BLM, the gene mutated in Bloom syndrome, encodes a DNA helicase of the RecQ family.

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Müller, S., Hoege, C., Pyrowolakis, G. et al. Sumo, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol 2, 202–210 (2001). https://doi.org/10.1038/35056591

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