Eukaryotic cells utilise the dynamic addition and removal of SUMO, a small ubiquitin‐like modifier (UBL), to modulate protein functions, interactions and localisation. Protein SUMOylation involves a cascade of dedicated enzymes that facilitate the covalent modification of specific lysine residues on target proteins with monomers or polymers of SUMO. The cellular homeostasis of SUMOylated proteins is also regulated by SUMO proteases and SUMO‐targeted ubiquitin ligase (STUbLs). SUMO proteases cleave SUMO from modified proteins. In contrast, STUbLs ubiquitinate proteins modified with SUMO chains. Recent data suggests that ubiquitination via STUbLs effects the turnover of SUMOylated proteins as well as the spatio‐temporal composition of complexes that contain SUMO‐modified proteins. Defects in the controlled addition, removal and turnover of SUMO‐modified proteins greatly affect cellular fitness and contribute to developmental defects, cancer and protein aggregation disorders.

Key Concepts

  • SUMO encodes a small ubiquitin‐like modifier that is covalently attached to lysines in target proteins.
  • SUMOylation, the process of SUMO conjugation to a target protein, frequently occurs on a lysine situated in a SUMOylation consensus site.
  • SUMO conjugates can be removed from target proteins by SUMO‐specific proteases.
  • Vertebrates express three different SUMO isoforms: SUMO1, SUMO2 and SUMO3, encoded by three different genes.
  • SUMOs can form polymers via internal SUMOylation sites in SUMO2 and SUMO3.
  • Several proteins can bind non‐covalently to SUMOs via SUMO interaction motifs (SIMs).
  • A finely balanced SUMOylation/de‐SUMOylation system is required for eukaryotic life.
  • Cross‐talk between SUMOylation and ubiquitination plays a critical in the turnover of some SUMOylated proteins as well as the spatiotemporal composition of complexes that contain SUMO‐modified proteins.

Keywords: SUMO; ubiquitin; STUbL; RNF4; Slx5

Figure 1. SUMOylation. (a) The SUMO precursor is rendered conjugation‐competent by processing through a SUMO protease (Ulp/SENP). In an ATP‐dependent reaction, the conjugation‐competent SUMO is transferred to an activating enzyme (E1), handed off to an conjugating enzyme (E2) and finally transferred to the substrate in a reaction that frequently requires a SUMO ligase (E3). SUMO chains on substrates are generated by multiple E1/E2/E3 cycles and depend on internal lysines in SUMO. SUMO and SUMO chains can be pruned by SUMO proteases. SUMO chains play an important role in the interaction with other proteins that contain SIMs to interact with SUMOylated proteins. (b) Depiction of an isopeptide bond through a lysine side chain of the substrate and the carboxy‐terminal glycine of the processed SUMO protein.
Figure 2. Consequences of SUMOylation. SUMO E1, E2 and E3 enzymes are involved in the covalent modification of proteins with monomeric SUMO or polymeric SUMO chains. SUMOylation can modulate the activity, localisation and interactions of a modified protein. STUbLs target and ubiquitinate proteins modified with SUMO chains, resulting in the formation of hybrid SUMO/ubiquitin chains. These modifications can be reversed by the activity of SUMO proteases (Ulp/SENP) or deubiquitinating enzymes (DUB). Ultimately, hybrid SUMO/ubiquitin chains lead to proteasome‐mediated degradation, either directly or after recruitment of other factors that disassemble and remodelling protein complexes.
Figure 3. STUbL‐mediated ubiquitylation of SUMOylated proteins. Slx5 and Slx8 are RING‐domain proteins that heterodimerise to form a STUbL complex (mammalian RNF4 forms a homodimer). Slx5 is the targeting subunit of this complex and contains at least four SIMs (\|/) that facilitate its binding to SUMOylated substrates (red protein with a chain of green SUMO monomers). A ubiquitin E2, Ubc4 or Ubc6, is required to ubiquitylate SUMOylated proteins in a reaction dependent on RING domains in both Slx5 and Slx8.
Figure 4. STUbL‐mediated degradation of the nuclear pool of SUMOylated Siz1. At the onset of mitosis, the SUMO ligase Siz1 becomes phophorylated (p) via an unknown kinase and exported to the cytosol via the karyopherin Msn5. In msn5Δ mutants (x), SUMOylated Siz1 acumulates in the nucleus, becomes ubiquitylated by the STUbL Slx5/Slx8 and is degraded.
Figure 5. STUBL‐mediated rearrangement of a protein complex in the nucleus. (I) SUMOylated proteins can accumulate in the nucleus, possibly as part of a protein/DNA complex. Examples described in this review include SUMOylated Siz1, Ataxin and several DNA repair proteins. (II) STUbls are recruited to proteins modified with SUMO chains resulting in the formation of hybrid SUMO/ubiquitin chains. (III) The formation of hybrid SUMO/ubiquitin chains on the STUbL target proteins may lead to targeting, extraction and disassembly of the associated protein/DNA complex, possibly via the disassemblase Cdc48. The extracted ubiquitylated protein may be subject to proteasome‐mediated degradation, while SUMO and ubiquitin chains are cleaved and degraded.


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Further Reading

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Kerscher, Oliver(Feb 2016) SUMOylation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021849.pub2]