IN THE ABSENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES, INVARIANT CHAIN IS TRANSLOCATED TO LATE ENDOCYTIC COMPARTMENTS BY AUTOPHAGY

It has been suggested that the cytoplasmic amino-terminal tail of inva riant chain (Ii) contains a sorting signal that directs trafficking of the major histocompatibility complex (MHC) class II: Ii oligomeric co mplex to endocytic compartments. This model is based, in part, on the observation that in the absence of MHC class II molecules, Ii is detec table in lysosomal structures, a phenotype that is dependent on an int act NH2 terminus. However, the route by which Ii gains access to endos omal compartments in the absence of class II molecules remains uncerta in. Here we report a mechanism that localizes Ii in lysosomal compartm ents independently of class II. We show that murine Ii can be detected by immunofluorescence within late endocytic compartments of stably tr ansfected Ltk(-) mouse fibroblasts. Immunochemical studies indicate th at degradation of Ii in these cells is sensitive to the lysosomotropic agent ammonium chloride,yet the majority of Ii that undergoes this ap parent lysosomal degradation is sensitive to the enzyme endoglycosidas e H. This finding suggests that Ii may reach the lysosomal compartment by a route that bypasses the Golgi complex. Consistent with this poss ibility, we found that in contrast to Ii which is complexed to class I I molecules, transport of free Ii to lysosomes is prevented by 3-methy ladenine. an inhibitor of the autophagic pathway of protein degradatio n, a process which involves direct transport from the endoplasmic reti culum to lysosomes. These data suggest the route of transport that lea ds to endosomal localization of Ii in the absence of class II is disti nct from that taken when expressed with class II. This forces a re-eva luation of the concept that the cytosolic tail of Ii contains a domina nt Golgi-to-endosomal sorting signal.