Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation is essential for maintenance of mammary stem cell activity

• Published in: Cell reports (Cambridge) Vol. 43; no. 9; p. 114762
• Main Authors: Chen, Weizhen, Guo, Luyao, Wei, Wei, Cai, Cheguo, Wu, Gaosong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-09-2024; Elsevier
• Subjects: CP: Developmental biology; CP: Stem cell research; Gpm6a; mammary gland development; mammary stem cell; Procr; Zdhhc1; Zdhhc2; Procr; mammary gland development; Gpm6a; CP: Stem cell research; mammary stem cell; CP: Developmental biology; Zdhhc1; Zdhhc2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114762

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.
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•Loss of Gpm6a hinders mammary gland development and reduces the activity of aMaSCs•Gpm6a deficiency disrupts Procr protein stability by inhibiting the formation of lipid rafts•Palmitoylation of Gpm6a, mediated by Zdhhc1 and Zdhhc2, is crucial for the aMaSC activity
Chen et al. demonstrate that Gpm6a deficiency reduces the activity of adult MaSCs. Gpm6a regulates the stability of the Procr protein by mediating the formation of lipid rafts. The palmitoylation of Gpm6a, facilitated by Zdhhc1 and Zdhhc2, is essential for Procr protein stability and adult MaSC activity.