Abstract
The invariant chain (Ii) targets major histocompatibility complex class II molecules to an endocytic processing compartment where they encounter antigenic peptides. Analysis of Ii-transferrin receptor chimeras expressed in polarized Madin-Darby canine kidney (MDCK) cells shows that the Ii cytoplasmic tail contains a dihydrophobic basolateral sorting signal, Met16-Leu17, which is recognized in both the biosynthetic and endocytic pathways. Pro15-Met16-Leu17 has previously been identified as one of two dihydrophobic Ii internalization signals active in non-polarized cells. Pro15 is also required for endocytosis in MDCK cells but not for basolateral sorting, indicating that the internalization signal recognized at the plasma membrane is distinct from the sorting signal recognized by basolateral sorting machinery. Another dihydrophobic sequence, Leu7-Ile8, is required for rapid internalization of the chimeric receptors in MDCK cells but not for basolateral sorting, providing further evidence that the structural requirements for basolateral sorting and internalization differ. Deletion analysis suggests that basolateral sorting of newly synthesized Ii-TR chimeras is also mediated by the membrane-proximal region of the Ii cytoplasmic tail. However, this region does not promote polarized basolateral recycling, indicating that the structural requirements for polarized sorting in the biosynthetic and endocytic pathways are not identical.
Highlights
Two basolateral sorting signals have been identified which are similar to dihydrophobic sorting signals that are known to mediate delivery to the endocytic pathway directly from the biosynthetic pathway or from the plasma membrane via endocytosis
We have investigated the sorting of invariant chain (Ii) in epithelial cells by analyzing the trafficking of Ii-transferrin receptor (TR) chimeras expressed in Madin-Darby canine kidney (MDCK) cells
By analysis of mutant Ii-TR chimeras, we demonstrate that a dihydrophobic sorting signal consisting of Met16Leu17 functions as a basolateral sorting signal which is required for polarized sorting in the endocytic pathway and is involved in basolateral sorting in the biosynthetic pathway
Summary
Two basolateral sorting signals have been identified which are similar to dihydrophobic sorting signals that are known to mediate delivery to the endocytic pathway directly from the biosynthetic pathway or from the plasma membrane via endocytosis (reviewed in Ref. 14). The steady-state cell-surface distributions of Ii-TR chimeras in filter-grown MDCK monolayers were subsequently determined by measuring the binding of 125I-labeled human Tf at the apical and basolateral surfaces at 4 °C. a chimera (IiCT) consisting of the 30-residue amino-terminal cytoplasmic tail of Ii (p33 isoform) and the transmembrane and extracellular domains of TR was localized predominantly at the basolateral surface, similar to the polarized cell-surface distribution of the wild-type TR [31], demonstrating that the cytoplasmic tail of Ii contains basolateral sorting information.
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