Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalization

The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+-dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR.

Automated summary

The naked mole-rat is of interest to aging research due to its resistance to age-associated diseases like cancer. In this study, it was found that mature ADAM10 is expressed in the skin fibroblasts of naked mole-rats, and the ionomycin can increase the localization of ADAM10 on the cell surface. However, ADAM10-mediated cleavage of CD44 and betacellulin was not observed in the naked mole-rat fibroblasts, unlike in mouse fibroblasts where it was induced by ionomycin. Overexpression of ANO6, a Ca2+-dependent phospholipid scramblase, increased phosphatidylserine exposure and rescued ADAM10 sheddase activity and cell migration in naked mole-rat fibroblasts in an ADAM10-dependent manner.