SUMO: regulating the regulator

Abstract

Post-translational modifiers of the SUMO (Small Ubiquitin-related Modifier) family have emerged as key regulators of protein function and fate. While the past few years have seen an enormous increase in knowledge on SUMO enzymes, substrates, and consequences of modification, regulation of SUMO conjugation is far from being understood. This brief review will provide an overview on recent advances concerning (i) the interplay between sumoylation and other post-translational modifications at the level of individual targets and (ii) global regulation of SUMO conjugation and deconjugation.

Figure 1

The SUMO pathway. All SUMO isoforms are synthetized as a precursor, containing a C-terminal extension, which is cleaved by specific hydrolases. Mature SUMO is then activated by formation of a thioester bond between its C-terminal glycine and the catalytic cysteine of the Uba2 subunit from the E1 activating enzyme (Aos1/Uba2). This step requires ATP hydrolysis. SUMO is then tranfered to the catalytic cysteine of the E2 activating enzyme Ubc9. The last step of the conjugating cascade consists in the transfer of SUMO from Ubc9 to the ε-NH2 group of a lysine side chain (isopeptide bond formation). Efficient modification usually requires E3 ligases. SUMOylation is a reversible and highly dynamic modification due to the presence of specific cysteine proteases of the Ulp/Senp family that cleave the isopeptide bond.

Figure 2

Regulation of SUMOylation through target modification. Distinct post-translational modifications of the target protein can affect its sumoylation. A) Competition with other lysine-directed modifications such as ubiquitinylation of acetylation abolishes sumoylation. B) Phosphorylation can act both as a positive and a negative regulator of sumoylation. Enhanced sumoylation has been observed, e.g., when the phosphorylated residue is part of an extended SUMO acceptor site, the PDSM (Phosphorylation Dependant SUMO Motif; with the sequence motif ΨKxExxSP [30]).

Figure 3

Global regulation of the conjugating machinery. A) The Gam1 protein from CELO adenovirus reduces E1 and E2 enzyme levels [47]. The resulting global desumoylation correlates with increased transcriptional activity, which is due, at least in part, to desumoylation of transcription factors such as Sp3. B) H₂O₂ inhibits SUMO conjugation by inducing the formation of a disulfide bond between the catalytic cysteines of the E1 and E2 enzymes. Depending on the source and dose of H₂O₂ (applied exogenously or produced endogenously) this results in local desumoylation of specific proteins or global desumoylation [52].