Sumoylation differentially regulates Sp1 to control cell differentiation

Authors

Lili Gong, University of Nebraska Medical Center, Omaha, NE
Wei-Ke Ji, University of Nebraska Medical Center, Omaha, NE
Xiao-Hui Hu, University of Nebraska Medical Center, Omaha, NE
Wen-Feng Hu, University of Nebraska Medical Center, Omaha, NE
Xiang-CHeng Tang, University of Nebraska Medical Center, Omaha, NE
Zhao-Xia Huang, Hunan Normal University, Changsha, Hunan
Ling Li, Hunan Normal University, Changsha, Hunan
Mugen Liu, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei
Shi-Hua Xiang, University of Nebraska-LincolnFollow
Erxi Wu, North Dakota State University, Fargo, ND
Zachary Woodward, University of Nebraska Medical Center, Omaha, NE
Yi-Zhi Liu, Sun Yat-Sen University
Quan Dong Nguyen, University of Nebraska Medical Center, Omaha, NE
David Wan-Cheng Li, University of Nebraska Medical Center, Omaha, NE

Document Type

Article

Date of this Version

2014

Citation

PNAS April 15, 2014 vol. 111 no. 15

Comments

Copyright 2014 Gong et al.

Abstract

The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as β-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to β-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.