The alternate N-terminal sequence of rat androgen-binding protein/sex hormone-binding globulin contains a nuclear targeting signal

Androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) is an extracellular carrier protein of androgens and estrogens. The protein regulates the bioavailability of sex steroids, and expanding evidence suggests that it also acts as a hormone. ABP/SHBG is secreted by Sertoli cells and hepatocytes using a signal peptide. An alternate messenger RNA encodes a nonsecreted form of ABP/SHBG (Alt-ABP/SHBG) that has a unique N-terminal amino acid sequence. In this study, we report that the alternate N-terminal sequence targets Alt-ABP/SHBG to the nucleus instead of the endoplasmic reticulum. The recombinant Alt-ABP/SHBG expressed in COS-7 cells was located in the nucleus, whereas recombinant cellular ABP/SHBG was primarily cytoplasmic. Neither dihydrotestosterone nor estradiol had any detectable effect on the ABP/SHBG or Alt-ABP/SHBG cellular location. Although the function of the nuclear Alt-ABP/SHBG is unknown, it may act as a modulator of androgen receptor- and/or estrogen receptor-mediated gene regulation.