Liu Sisi, Long Jianyin, Yuan Bo, Zheng Mingjie, Xiao Mu, Xu Jianming, Lin Xia, Feng Xin-Hua
From the Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China,; the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, and; the Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, and.
J Biol Chem. 2016 Nov 18;291(47):24418-24430. doi: 10.1074/jbc.M116.755850. Epub 2016 Oct 4.
SNIP1 (Smad nuclear interacting protein 1) is a transcription repressor for the TGF-β and NF-κB signaling pathways through disrupting the recruitment of co-activator p300. However, it is unclear how the functions of SNIP1 in the TGF-β 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, Lys, and Lys, with Lys being the major SUMO modification site. SUMOylation of SNIP1 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 TGF-β 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-β target genes PAI-1 and MMP2 and eventually enhances TGF-β-regulated cell migration and invasion.
SNIP1（Smad核相互作用蛋白1）是一种转录抑制因子，通过破坏共激活因子p300的募集来抑制转化生长因子-β（TGF-β）和核因子κB（NF-κB）信号通路。然而，目前尚不清楚SNIP1在TGF-β信号通路中的功能是如何被调控的。我们目前的研究表明，SNIP1在体外和体内可在三个赖氨酸位点（赖氨酸、赖氨酸和赖氨酸）被小泛素样修饰物（SUMO）共价修饰，其中赖氨酸是主要的SUMO修饰位点。SNIP1的SUMO化可被SUMO E3连接酶PIAS蛋白增强，并被SUMO蛋白酶SENP1/2抑制。此外，我们发现SNIP1的SUMO化减弱了其在TGF-β信号通路中的抑制作用，因为SUMO共轭形式的SNIP1破坏Smad复合物形成以及p300与Smads之间相互作用的能力受损。随后，SNIP1的SUMO化导致SNIP1介导的对TGF-β靶基因PAI-1和MMP2表达抑制的丧失，并最终增强TGF-β调节的细胞迁移和侵袭。
