The modification of
proteins with farnesyl or geranylgeranyl
lipids, a process called protein prenylation, facilitates interactions of
proteins with membrane surfaces. Protein prenylation is carried out by a pair of cytosolic
enzymes,
protein farnesyltransferase (FTase) and
protein geranylgeranyltransferase type I (
GGTase-I). FTase and
GGTase-I have attracted interest as therapeutic targets for both
cancer and
progeria, but very little information exists on the importance of these
enzymes for homeostasis of normal tissues. One study actually suggested that FTase is entirely dispensable. To explore the importance of the
protein prenyltransferases for normal tissues, we used conditional knockout alleles for Fntb and Pggt1b (which encode the beta-subunits of FTase and
GGTase-I, respectively) and a
keratin 14-Cre transgene to create mice lacking FTase or
GGTase-I in skin keratinocytes. Keratinocyte-specific Fntb knockout mice were viable but developed severe
alopecia. Although hair follicles appeared normal during development, they were morphologically abnormal after birth, and ultrastructural and immunohistochemical studies revealed many apoptotic cells. The interfollicular epidermis of Fntb-deficient mice appeared normal; however, keratinocytes from these mice could not proliferate in culture. As expected, non-farnesylated
prelamin A and non-farnesylated DNAJA1 accumulated in Fntb-deficient keratinocytes. Keratinocyte-specific Pggt1b knockout mice survived development but died shortly after birth. Like Fntb-deficient keratinocytes, Pggt1b-deficient keratinocytes did not proliferate in culture. Thus, both FTase and
GGTase-I are required for the homeostasis of skin keratinocytes.