A SIM-ultaneous role for SUMO and ubiquitin

doi:10.1016/j.tibs.2008.02.001

Trends in Biochemical Sciences

Volume 33, Issue 5, May 2008, Pages 201-208

https://doi.org/10.1016/j.tibs.2008.02.001 Get rights and content

Ubiquitin and ubiquitin-like proteins (Ubls) share a β-GRASP fold and have key roles in cellular growth and suppression of genome instability. Despite their common fold, SUMO and ubiquitin are classically portrayed as distinct, and they can have antagonistic roles. Recently, a new family of proteins, the small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligases (STUbLs), which directly connect sumoylation and ubiquitylation, has been discovered. Uniquely, STUbLs use SUMO-interaction motifs (SIMs) to recognize their sumoylated targets. STUbLs are global regulators of protein sumoylation levels, and cells lacking STUbLs display genomic instability and hypersensitivity to genotoxic stress. The human STUbL, RNF4, is implicated in several diseases including cancer, highlighting the importance of characterizing the cellular functions of STUbLs.

Section snippets

Ubiquitin-like domains

Covalent post-translational modifications regulate protein function and are collectively required for cell viability. Ubiquitin and ubiquitin-like proteins (Ubls; see Glossary), including SUMO (small ubiquitin-like modifier), are a subset of these modifications [1]. Despite their lack of sequence similarity, ubiquitin and SUMO are small, single-domain proteins that share the same β-GRASP fold 2, 3. However, their surface residues and charge distributions are significantly different, supporting

The E3 ligases

Multiple ubiquitin and SUMO E3 ligases exist in humans, providing target-protein selectivity. There are ∼1000 ubiquitin ligases in the human genome, belonging to distinct classes based on their structure and substrate specificity. The largest class is the RING (really interesting new gene)-finger domain ubiquitin ligases, members of which stimulate transfer of ubiquitin from the E2 enzyme to the substrate [12]. RING-finger proteins are zinc-finger variants that also coordinate two zinc atoms,

Identification of SUMO-targeted ubiquitin ligases

A novel family of RING-finger ubiquitin ligases that recognize sumoylated substrates has recently been identified 7, 23, 24, 25, 26. Proteins only now known to belong to this STUbL family were first observed in budding yeast. Two RING-finger proteins, Slx5p (also known as Hexose metabolism-related protein Hex3p) and Slx8p, were identified as gene products that are essential for the viability of budding yeast lacking the Sgs1p DNA helicase [27]. Slx5p and Slx8p are required for cellular survival

STUbLs use SUMO-interaction motifs

The utilization of SIMs is the key difference between STUbLs and other RING-finger proteins 23, 24, 25, 26. SIMs bind to SUMO in a non-covalent manner and contain short unstructured hydrophobic stretches, which are sometimes flanked by acidic amino acids that might contribute to binding specificity 8, 38. SIMs are typically observed in proteins with known roles in sumoylation; a notable example includes the promyelocytic leukemia (PML) SIM–SUMO interactions that are required to form PML

STUbLs regulate sumoylation-pathway homeostasis

The ubiquitin ligase activity of STUbLs mediates sumoylation-pathway homeostasis 23, 24, 25, 26, 34. Therefore, by ubiquitylating and promoting desumoylation and/or degradation of sumoylated target proteins, STUbLs provide an unanticipated direct crosstalk between the ubiquitin and SUMO pathways. The lethal phenotype of an slx8⁺ deletion in fission yeast is suppressed by concomitant deletion of the major E3 SUMO ligase pli1⁺, thereby demonstrating the specificity of STUbLs in regulating

Mechanisms of STUbL function

STUbLs might regulate sumoylation-pathway homeostasis by targeting components of the sumoylation machinery and/or SUMO conjugates – STUbLs might ubiquitylate and regulate the activities of the SUMO E1, E2 or E3 enzymes, analogous to the inhibition of the ubiquitin-conjugating enzyme E2–25k by SUMO conjugation [46]. Evidence exists for the direct regulation of SUMO-conjugated target proteins by STUbLs. Studies in Dictyostelium discoideum (slime mold) identified a kinase, MEK1 (MAPK/ERK kinase

STUbL targets in genome stability

Many yeast SUMO substrates are nuclear proteins, indicating the likely location of STUbL targets. Sumoylated proteins are often involved in the maintenance of chromosomal integrity and genome stability through multiple chromosome segregation, replication and DNA-repair pathways 5, 49, 50. One SUMO substrate is the DNA homologous recombination repair (HRR) factor Rad52 (named for radiation sensitive) that is sumoylated in both yeast and human cells; in yeast, sumoylation modulates Rad52p

Concluding remarks and future perspectives

The exciting recent discovery of STUbL proteins opens the door for many further analyses. Importantly, what are the targets of RNF4, the human STUbL? These targets might include transcription factors, which are directly regulated by Ubls through altered subcellular localization, degradation, or differential recruitment of activators and repressors 5, 55. For example, members of the steroid-receptor transcription factor family undergo both positive and negative regulation by Ubls. This family

Acknowledgements

We thank The Scripps Research Cell Cycle and Structural Biology groups for their support. Work in the laboratory of M.N.B. is supported by NIH grant GM068608 and research on DNA-damage responses, replication stress and the RecQ helicases in the laboratory of J.A.T. is supported by NIH grant CA104660.

Glossary

E1, E2 and E3 enzymes: an E1-activating enzyme (with ATP) adenylates the C-terminal carboxyl group of ubiquitin or Ubl, which forms a high-energy ubiquitin–AMP or Ubl–AMP intermediate. This intermediate is then attacked by the E1 active-site cysteine, forming an E1-ubiquitin or E1-Ubl thioester. The activated ubiquitin or Ubl is transferred to the active-site cysteine of the E2-conjugating enzyme. The ubiquitin or Ubl moiety is then ligated to an acceptor lysine in a target protein in a process

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Posttranslational modifications are key regulators of protein function and interactions. One of these modifications, small ubiquitin-like modifier (SUMO), is a reversible modification that has a significant impact on cellular function. Though highly transient, SUMO modification has long-lasting effects. SUMOylation regulates key nuclear processes that include replication, maintenance of genome integrity, transcription, splicing, and transport. In recent years, the critical importance of SUMO modification of proteins at the synapse has also emerged and a significant number of neurodegenerative disease proteins have been shown to be subject to SUMO modification including alpha-synuclein, tau, Amyloid Precursor Protein (APP), SOD1, and a number of CAG repeat disease–associated proteins (Ataxin-1, Ataxin-7, Androgen Receptor, and Huntingtin) among others. Further, SUMO modification has roles in modulating liquid–liquid transitions, including stress granules, and in protein and organelle clearance. Here we review the current status of SUMOylation as it relates to key mechanisms implicated in HD.
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Trends in Biochemical Sciences

ReviewA SIM-ultaneous role for SUMO and ubiquitin

Section snippets

Ubiquitin-like domains

The E3 ligases

Identification of SUMO-targeted ubiquitin ligases

STUbLs use SUMO-interaction motifs

STUbLs regulate sumoylation-pathway homeostasis

Mechanisms of STUbL function

STUbL targets in genome stability

Concluding remarks and future perspectives

Acknowledgements

Glossary

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Annu. Rev. Cell Dev. Biol.

Review
A SIM-ultaneous role for SUMO and ubiquitin