A comprehensive compilation of SUMO proteomics

Key Points

  • Small ubiquitin-like modifier (SUMO)ylation is a ubiquitin-like post-translational modification that is technically challenging to study by mass spectrometry-based proteomics, owing to low modification stoichiometry and incompatibility with standard mass spectrometry approaches.

  • Over the past decade, several methods were developed to allow the identification of sumoylated proteins. Recently, novel methods were established that enable the identification of site-specific sumoylation, leading to the identification of thousands of modified Lys residues.

  • We have compiled and evaluated data of sumoylated proteins and sites from 22 proteomic studies and generated the most comprehensive sumoylation database to date.

  • The most abundantly sumoylated proteins are some of the most functionally interconnected proteins, indicating that sumoylation preferentially targets specific pathways and protein complexes and acts as a group modifier.

  • The regulation of the SUMO signal is more complex than previously appreciated, owing to the post-translational modification of SUMO family members by phosphorylation, acetylation and ubiquitylation.

  • With the availability of increasingly potent proteomic methods and equipment, our understanding of sumoylation and its functions can now be developed to match that of ubiquitylation, acetylation and phosphorylation.

Abstract

Small ubiquitin-like modifiers (SUMOs) are essential for the regulation of several cellular processes and are potential therapeutic targets owing to their involvement in diseases such as cancer and Alzheimer disease. In the past decade, we have witnessed a rapid expansion of proteomic approaches for identifying sumoylated proteins, with recent advances in detecting site-specific sumoylation. In this Analysis, we combined all human SUMO proteomics data currently available into one cohesive database. We provide proteomic evidence for sumoylation of 3,617 proteins at 7,327 sumoylation sites, and insight into SUMO group modification by clustering the sumoylated proteins into functional networks. The data support sumoylation being a frequent protein modification (on par with other major protein modifications) with multiple nuclear functions, including in transcription, mRNA processing, DNA replication and the DNA-damage response.

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Figure 1: The sumoylation system.
Figure 2: The dynamic SUMO proteome.
Figure 3: Sumoylated proteins are functionally interconnected.
Figure 4: SUMO functionality.
Figure 5: Modification of SUMO family members by other post-translational modifications produces complex signalling codes.

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Acknowledgements

The authors apologize to researchers whose work could not be cited owing to space constraints. The authors are grateful for support from the Netherlands Organization for Scientific Research (NWO) and the European Research Council.

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Correspondence to Alfred C. O. Vertegaal.

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Supplementary information

Supplementary information S1 (box)

Methods for SUMO proteomics (PDF 791 kb)

Supplementary information S2 (table)

A list of all proteins identified to be SUMO target proteins by any of 22 published proteomic studies or low-throughput studies. (XLSX 988 kb)

Supplementary information S3 (table)

A list of all lysines identified to be SUMOylated by any of 11 published proteomic studies or low-throughput studies. (XLSX 2027 kb)

Supplementary information S4 (box)

Methods used for the analysis of SUMO proteomics data (PDF 424 kb)

Supplementary information S5 (table)

A list of all SUMO target proteins identified by SUMOylated lysine, by at least one of 11 published proteomic studies. (XLSX 478 kb)

Supplementary information S6 (box)

Comparison of published and reprocessed sites (PDF 191 kb)

Supplementary information S7 (box)

Technical comparison of SUMO site purification methods (PDF 212 kb)

Supplementary information S8 (box)

Comparison of individual studies (PDF 503 kb)

Supplementary information S9 (box)

Secondary PCA analysis (PDF 917 kb)

Supplementary information S10 (box)

Global effects of stress on the SUMOylated proteome (PDF 269 kb)

Supplementary information S11 (table)

A list of terms, based on Gene Ontology and general keywords, applicable to SUMO target proteins that are globally upregulated or downregulated in SUMOylation in response to proteotoxic stress, as profiled over multiple proteomic studies. (XLSX 32 kb)

Supplementary information S12 (figure)

SUMOylated proteins are functionally interconnected. (PDF 656 kb)

Supplementary information S13 (table)

A list of enriched or depleted terms, based on Gene Ontology, Corum, KEGG, Pfam and general keywords, globally applicable to all SUMO target proteins identified by at least three proteomic studies. (XLSX 245 kb)

Supplementary information S14 (figure)

An unbiased SUMO consensus motif. (PDF 358 kb)

PowerPoint slides

Glossary

SUMO group modification

Simultaneous alteration of a cluster of functionally related proteins by a small ubiquitin-like modifier (SUMO). The cluster contains proteins with SUMO-conjugation sites and SUMO-interaction motifs, which mediate protein–protein interactions.

KXE-type motifs

Small ubiquitin-like modifier (SUMO)ylation consensus motifs consisting of a SUMO-conjugated Lys residue and a Glu residue separated by one amino acid.

E4 elongase

A small ubiquitin-like modifier (SUMO) ligase that extends SUMO polymers.

Principal component analysis

(PCA). An analysis tool used to determine how related or distinct complex data sets are from each other.

Methyl methanesulfonate

An alkylating agent that adds methyl groups to the DNA, thereby causing DNA damage.

Hydroxyurea

A compound that causes DNA replication-dependent damage by inhibiting ribonucleotide reductase, thereby decreasing the production of deoxyribonucleotides.

[IVL]KXE motif

A small ubiquitin-like modifier (SUMO)ylation consensus motif consisting of an inwardly oriented hydrophobic residue, a SUMO-conjugated Lys residue and a Glu residue. This motif is a strong indication for sumoylation and is modified at a relatively high stoichiometry.

Inverted sumoylation consensus motif

(ISCM). A small ubiquitin-like modifier (SUMO)ylation motif in which the acidic residue precedes the sumoylated Lys.

Tryptic remnant

A piece of a protein modification that remains attached to a target protein after digestion of the protein sample by the endoprotease trypsin.

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Hendriks, I., Vertegaal, A. A comprehensive compilation of SUMO proteomics. Nat Rev Mol Cell Biol 17, 581–595 (2016). https://doi.org/10.1038/nrm.2016.81

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