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Review
. 2022 Jul 20;23(14):8012.
doi: 10.3390/ijms23148012.

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

Nieves Lara-Ureña  1 , Vahid Jafari  1 , Mario García-Domínguez  1
Affiliations
Review

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

Nieves Lara-Ureña et al. Int J Mol Sci. .

Abstract

SUMOylation is a post-translational modification that has emerged in recent decades as a mechanism involved in controlling diverse physiological processes and that is essential in vertebrates. The SUMO pathway is regulated by several enzymes, proteases and ligases being the main actors involved in the control of sumoylation of specific targets. Dysregulation of the expression, localization and function of these enzymes produces physiological changes that can lead to the appearance of different types of cancer, depending on the enzymes and target proteins involved. Among the most studied proteases and ligases, those of the SENP and PIAS families stand out, respectively. While the proteases involved in this pathway have specific SUMO activity, the ligases may have additional functions unrelated to sumoylation, which makes it more difficult to study their SUMO-associated role in cancer process. In this review we update the knowledge and advances in relation to the impact of dysregulation of SUMO proteases and ligases in cancer initiation and progression.

Keywords: SUMO; cancer; ligase; protease; regulation; transcription.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The sumoylation pathway. E1 enzyme (SAE1-UBA2 heterodimer), by using ATP, activates mature SUMO and transfers it to the E2 enzyme UBC9, which ultimately transfer SUMO to targets, either directly, or more frequently, assisted by an E3 SUMO ligase. SUMO maturation and scission from targets are performed by specific SUMO proteases. Maturation involves the exposition of two tandem Gly (G) residues at the C-terminus of mature SUMO. Activation and transfer to UBC9 involve the formation of thioester bonds between C-terminus of mature SUMO and specific Cys (C) residues at catalytic sites of E1 and E2, respectively. Defined Lys (K) residues at targets are the final SUMO acceptors for covalent attachment. Proteases and ligases are linked to target selection-associated steps in the sumoylation pathway.
Figure 2
Figure 2
The SENP family. (A) Schematic representation of human SENP proteins with the C-terminal catalytic domain and the key His (H) and Cys (C) residues. HP1 interacting domains are also shown on SENP7, for which two isoforms have been described: large (SENP7L) and short (SENP7S), lacking the latter of one of the HP1 interacting motifs. The number of amino acids is also shown for each protein. (B) Endopeptidase (maturation) and isopeptidase (deconjugation and editing) activities for each SENP protein are shown. Strength of activity in relation to paralog preference is indicated for maturation activity. (C) Localization of SENP proteins to different cellular compartments is schematically represented. NPC, nuclear pore complex.
Figure 3
Figure 3
The PIAS family. (A) Schematic representation of human PIAS proteins. The SP-RING and SAP domains, together with the PINIT region, the acidic stretch (AC) and the C-terminal Ser/Thr (S/T) rich region, are shown. Two alternative isoforms, α and β, have been classically described for PIAS2. The number of amino acids is also shown for each protein. (B) Proposed ligase mechanisms using PIAS1 and RanBP2 as models. In the case of PIAS1, simultaneous binding of target and SUMO-loaded UBC9 through different domains may facilitate SUMO transfer to the target. The SP-RING is important for UBC9 binding but may also mediate other protein interactions for additional functions. Other domains, like the SAP domain, may recruit SUMO targets, but it is also involved in additional functions. The minimal protein region required for ligase activity is indicated with brackets. In the case of RanBP2, interaction of SUMO and UBC9 with a SIM and the 50-amino acid internal repeat (IR) 1, respectively, should position the thioester bond in the appropriate conformation for efficient transfer of SUMO to the target, which is not required to directly interact with the ligase. RB, Ran binding domain.
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