Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation is essential for maintenance of mammary stem cell activity
Weizhen Chen,
Luyao Guo,
Wei Wei,
Cheguo Cai,
Gaosong Wu
Affiliations
Weizhen Chen
Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan 430071, China
Luyao Guo
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China
Wei Wei
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China
Cheguo Cai
Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan 430071, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Corresponding author
Gaosong Wu
Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan 430071, China; Corresponding author
Summary: Adult mammary stem cells (aMaSCs) are vital to tissue expansion and remodeling during the process of postnatal mammary development. The protein C receptor (Procr) is one of the well-identified surface markers of multipotent aMaSCs. However, an understanding of the regulatory mechanisms governing Procr’s protein stability remains incomplete. In this study, we identified Glycoprotein m6a (Gpm6a) as a critical protein for aMaSC activity modulation by using the Gpm6a knockout mouse model. Interestingly, we determined that Gpm6a depletion results in a reduction of Procr protein stability. Mechanistically, Gpm6a regulates Procr protein stability by mediating the formation of lipid rafts, a process requiring Zdhhc1 and Zdhhc2 to palmitate Gpm6a at Cys17,18 and Cys246 sites. Our findings highlight an important mechanism involving Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation for the regulation of Procr stability, aMaSC activity, and postnatal mammary development.
