SUMOylation of GPS2 protein regulates its transcription-suppressing function

Abstract

GPS2 can be modified by SUMO-1. SUMOylation stabilizes GPS2 protein and enhances its ability to suppress transcription, as well as promoting its ability to inhibit ERα-mediated transcription by increasing its association with SMRT, as demonstrated in MCF-7 and T47D cells.

Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation

“…2F, mutating K71R significantly decreases the direct interaction between GPS2 and TBL1 in a GST pulldown assay, whereas no changes were noticed upon mutation of K45R alone. Together, these data indicate that the integrity of Lys-71 is required for the direct interaction between GPS2 and TBL1 and confirm that the reported decreased half-life of the double mutant (19) is likely caused by decreased interaction between GPS2 and TBL1 but in a sumoylation-independent manner. Stabilization of GPS2 upon coexpression with TBL1 in bacteria (Fig.…”

“…To further investigate how the interaction with TBL1 affects GPS2 stability and cellular localization, we focused on a recent paper reporting that sumoylation of GPS2 on Lys-45 and Lys-71 participates in regulating GPS2 interaction with TBL1 and repressive activity in the nucleus (19). Interestingly, substitution of Lys-45/71 with arginine residues (2KR mutant) appeared to affect GPS2 shuttling between the nucleus and cytoplasm (19).…”

“…Interestingly, substitution of Lys-45/71 with arginine residues (2KR mutant) appeared to affect GPS2 shuttling between the nucleus and cytoplasm (19). Because Lys-45 is located within the newly identified NLD, we considered the possibility that sumoylation contributes to regulating GPS2 stabilization and/or nuclear localization via interaction with TBL1.…”

“…To better understand these discrepancies, we tested sumoylation mutants equivalent to those described previously (K45R, K71R, and 2KR or K45/71R) (19) for direct interaction with TBL1. As shown in Fig.…”

“…1E), together with the report of a tight association between TBL1 and GPS2 in the assembly of the NCoR-SMRT core complex (28), suggests that the interaction among these cofactors may be required for proper protein folding and that GPS2-unregulated destabilization in the absence of TBL1 may result from reduced complex formation. However, the alternative hypothesis of GPS2 being actively degraded by the 26S proteasome via an ubiquitination-dependent mechanism also exists (3,8,19,22). To directly assess whether GPS2 instability in the absence of TBL1 was mediated by proteasomal degradation, we first looked for GPS2 polyubiquitination.…”