Targeting of protein ERGIC-53 to the ER/ERGIC/cis-Golgi recycling pathway

We show that targeting of ERGIC-53 cannot be explained by a simple retrieval mechanism, since proper localization required the lumenal and the cytoplasmic domains. The cytoplasmic domain possesses three determinants all of which are required for correct targeting within the ER-ERGIC-cis-Golgi recycling pathway: a functional di-lysine ER-retrieval signal, KKFF, a targeting determinant adjacent to the membrane, RSQQE, and two COOH-terminal phenylalanines that reduce the retrieval efficiency of the di-lysine signal and modulate the RSQQE targeting determinant. Thus the ER-retrieval signal, although critical for retaining ERGIC-53 in the ER-ERGIC-cis-Golgi recycling pathway, is not sufficient for the correct distribution throughout these compartments. Targeting of ERGIC-53 depends on a complex interplay of multiple determinants.