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Volume 272, Number 46, Issue of November 14, 1997 pp. 29127-29136
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Major Histocompatibility Complex Class II-dependent Unfolding, Transport, and Degradation of Endogenous Proteins

(Received for publication, May 5, 1997, and in revised form, August 14, 1997)

Gerald Aichinger ^§ , Lars Karlsson , Michael R. Jackson , Mikael Vestberg , John H. Vaughan ^** , Luc Teyton , Robert I. Lechler ^§ and Per A. Peterson

From the  R. W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, the  Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, the ^** Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92039, and the ^§ Department of Immunology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, W12 ONN London, United Kingdom

We have analyzed the ability of major histocompatibility (MHC) class II molecules to capture proteins in the biosynthetic pathway and whether this may be associated with MHC class II-dependent antigen processing. When coexpressed with HLA-DR 4 molecules in HeLa cells, influenza hemagglutinin was inhibited from folding and trimerization in the biosynthetic pathway, targeted to endosomal compartments, and rapidly degraded. Due to the interaction with MHC class II molecules, therefore, unfolded forms of hemagglutinin were bypassing the quality control mechanism of the secretory pathway. More important, however, the transport, endocytosis, and rapid degradation of unfolded hemagglutinin in the presence of MHC class II molecules suggest that proteins captured in the endoplasmic reticulum by class II molecules may become substrates for antigen processing and presentation to CD4-positive T cells. In insect cells we show that this phenomenon is not restricted to a few proteins such as hemagglutinin. A highly heterogeneous mixture of proteins from the endoplasmic reticulum including coexpressed hemagglutinin can form stable complexes with soluble HLA-DR and  chains that were transported into the supernatant. This mechanism may gain biological significance in abnormal situations associated with accumulation of unfolded or malfolded proteins in the endoplasmic reticulum, for example during viral infections.

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