SUMO Modification Reverses Inhibitory Effects of Smad Nuclear Interacting Protein-1 in TGF-β Responses

SNIP1 (Smad nuclear interacting protein 1) is a transcription repressor for the TGE-beta and NE-kappa B signaling pathways through disrupting the recruitment of co-activator p300. However, it is unclear how the functions of SNIP1 in the TGE-beta signaling pathway are controlled. Our present studies show that SNIP1 is covalently modified by small ubiquitin-like modifier (SUMO) in vitro and in vivo at three lysine sites: Lys(5), Lys(30), and Lys(108), with Lys(30) being the major SUMO modification site. SUMOylation of SNIP! is enhanced by SUMO E3 ligase PIAS proteins and inhibited by SUMO proteases SENP1/2. Furthermore, we find that SUMOylation of SNIP1 attenuates its inhibitory effect in TGE-beta signaling because the SUMO-conjugated form of SNIP1 exhibits impaired ability to disrupt the formation of Smad complex and the interaction between p300 and Smads. Subsequently, SUMOylation of SNIP1 leads to the loss of SNIP1-mediated inhibition on expression of the TGF-beta target genes PAI-1 and MMP2 and eventually enhances TGE-beta-regulated cell migration and invasion.