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© The Rockefeller University Press, 0021-9525/1997//51 $5.00
The Journal of Cell Biology, Volume 137, Number 1, , 1997 51-65

Article

Ii Chain Controls the Transport of Major Histocompatibility Complex Class II Molecules to and from Lysosomes



Valérie Brachet*, Graça Raposo*, Sebastian Amigorena*, and Ira Mellman{ddagger}

* Institut Curie, Section de Recherche Institut National de la Santé et de la Recherche Médicale CJF-95.01 and Centre National de la Recherche Scientifique UMR 144, 75231 Paris cedex 05, France; and {ddagger} Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520

Major histocompatibility complex class II molecules are synthesized as a nonameric complex consisting of three {alpha}β dimers associated with a trimer of invariant (Ii) chains. After exiting the TGN, a targeting signal in the Ii chain cytoplasmic domain directs the complex to endosomes where Ii chain is proteolytically processed and removed, allowing class II molecules to bind antigenic peptides before reaching the cell surface. Ii chain dissociation and peptide binding are thought to occur in one or more postendosomal sites related either to endosomes (designated CIIV) or to lysosomes (designated MIIC). We now find that in addition to initially targeting {alpha}β dimers to endosomes, Ii chain regulates the subsequent transport of class II molecules. Under normal conditions, murine A20 B cells transport all of their newly synthesized class II I-Ab {alpha}β dimers to the plasma membrane with little if any reaching lysosomal compartments. Inhibition of Ii processing by the cysteine/serine protease inhibitor leupeptin, however, blocked transport to the cell surface and caused a dramatic but selective accumulation of I-Ab class II molecules in lysosomes. In leupeptin, I-Ab dimers formed stable complexes with a 10-kD NH2-terminal Ii chain fragment (Ii-p10), normally a transient intermediate in Ii chain processing. Upon removal of leupeptin, Ii-p10 was degraded and released, I-Ab dimers bound antigenic peptides, and the peptide-loaded dimers were transported slowly from lysosomes to the plasma membrane. Our results suggest that alterations in the rate or efficiency of Ii chain processing can alter the postendosomal sorting of class II molecules, resulting in the increased accumulation of {alpha}β dimers in lysosome-like MIIC. Thus, simple differences in Ii chain processing may account for the highly variable amounts of class II found in lysosomal compartments of different cell types or at different developmental stages.

Abbreviations used in this paper: FFE, free flow electrophoresis; Ii, invariant; lamp, lysosomal-associated membrane protein; lgp, lysosomal glycoprotein; MHC, major histocompatibility complex; Tfn, transferrin.

Please address all correspondance to Sebastian Amigorena, Section de Recherche, INSERM CJF-95.01, 26 rue d'Ulm, 75231 Paris cedex 05, France. Tel.: (33) 1-42-34-63-89. Fax: (33) 1-42-34-63-82. e-mail: s.amigorena{at}curie.fr


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