A. Chervonsky et Aj. Sant, IN THE ABSENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES, INVARIANT CHAIN IS TRANSLOCATED TO LATE ENDOCYTIC COMPARTMENTS BY AUTOPHAGY, European Journal of Immunology, 25(4), 1995, pp. 911-918
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.