Forward Transport: 14-3-3 Binding Overcomes Retention in Endoplasmic Reticulum by Dibasic Signals

Proteins with dibasic retention motifs are subject to retrograde transport to endoplasmic reticulum (ER) by COPI-coated vesicles. As forward transport requires escape from ER retention, general release mechanisms have been expected. Here, KCNK3 potassium channels are shown to bear two cytoplasmic trafficking motifs: an N-terminal dibasic site that binds β-COP to hold channels in ER and a C-terminal “release” site that binds the ubiquitous intracellular regulator 14-3-3β on a nonclassical motif in a phosphorylation-dependent fashion to suppress β-COP binding and allow forward transport. The strategy appears to be common. The major histocompatibility antigen class II-associated invariant chain Iip35 exhibits dibasic retention, carries a release motif, and shows mutually exclusive binding of β-COP and 14-3-3β on adjacent N-terminal sites. Other retained proteins are demonstrated to carry functional 14-3-3β release motifs.