The amino-terminal domain of the lamin B receptor is a nuclear envelope targeting signal

protein of the inner nuclear membrane. It is synthesized without a cleavable amino-terminal signal sequence and composed of a nucleoplasmic aminoterminal domain of 204 amino acids followed by a hydrophobic domain with eight putative transmembrane segments. To identify a nuclear envelope targeting signal, we have examined the cellular localization by immunofluorescence microscopy of chicken LBR, its amino-terminal domain and chimeric proteins transiently expressed in transfected COS-7. Full-length LBR was targeted to the nuclear envelope. The aminoterminal domain, without any transmembrane segments, was transported to the nucleus but excluded from the nucleolus. When the amino-terminal domain of LBR was fused to the amino-terminal side of a transmembrane segment of a type II integral membrane protein of the ER/plasma membrane, the chimeric protein was targeted to the nuclear envelope, likely the inner nuclear membrane. When the aminoterminal domain was deleted from LBR and replaced by ot-globin, the chimeric protein was retained in the ER. These findings demonstrate that the aminoterminal domain of LBR is targeted to the nucleus after synthesis in the cytoplasm and that this polypeptide can function as a nuclear envelope targeting signal when located at the amino terminus of a type II integral membrane protein synthesized on the ER. T HE topology of integral membrane proteins synthesized on the ER is established by signal and stop transfer sequences that determine which domains traverse aqueous pores in the ER membrane and which domains remain localiT~d in the membrane (Blobel, 1980; Simon and Blobel, 1991) . Some of these proteins contain specific sequences that confer retention in the ER (Paabo et al., 1987; Nilsson et al., 1989; Jackson et ai., 1990) . Others are targeted to the cis-C-olgi network by ER-derived membrane vesicles, and some of these integral membrane proteins contain sequences that confer retention in the Golgi membranes (lVlachamer and Rose, 1987; Nilsson et al., 1991; Wong et al., 1992) . Most integral membrane proteins that reach the Golgi complex are sorted into different populations of membrane vesicles that emerge from the TGN to become secretory storage vesicles or to fuse with lysosomes or the plasma membrane (Grifiiths and Simons, 1986; Klausner, 1989; Kornfeld and Mellman, 1989; Rothman and Orci, 1992) . In epithelial cells, additional sorting mechanisms are operative that target protein-containing membrane vesicles to either the apical or basolateral membranes (Rodriguez-Boulan and Nelson, 1989) .