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

Cell Rep. 2024 Sep 17;43(9):114762. doi: 10.1016/j.celrep.2024.114762. Print 2024 Sep 24.

Abstract

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.

Keywords: CP: Developmental biology; CP: Stem cell research; Gpm6a; Procr; Zdhhc1; Zdhhc2; mammary gland development; mammary stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases* / genetics
  • Acyltransferases* / metabolism
  • Animals
  • Female
  • Humans
  • Lipoylation*
  • Mammary Glands, Animal* / cytology
  • Mammary Glands, Animal* / metabolism
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Knockout
  • Protein Stability
  • Stem Cells / cytology
  • Stem Cells / metabolism

Substances

  • Acyltransferases