EVIDENCE THAT BINDING-SITE OCCUPANCY IS NECESSARY AND SUFFICIENT FOR EFFECTIVE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS-II TRANSPORT THROUGH THE SECRETORY PATHWAY REDEFINES THE PRIMARY FUNCTION OF CLASS II-ASSOCIATED INVARIANT CHAIN PEPTIDES (CLIP)

Invariant chain (Ii) associates with newly synthesized class II molecu les in the endoplasmic reticulum (ER), an interaction that has been sh own to interfere with peptide binding to class II molecules. The class II-associated invariant chain peptide (CLIP) region (residues 81-104) of Ii is believed to mediate this inhibition by engaging the binding domain of class II Like an antigenic peptide. Together, these findings have given rise to a model in which CLIP association with the class I I groove acts to prevent inappropriate presentation of peptides import ed into the ER for association with major histocompatibility complex c lass I molecules. However, the properties of class II molecules synthe sized by cells lacking coexpressed Ii are at least superficially incon sistent with this paradigm in that they do not show clear evidence of peptide acquisition. At the same time, we have previously shown the sh ortest form of Ii still containing CLIP to play an essential role in r egulation of early class II molecule assembly and transport in the sec retory pathway. Using covalent peptide technology, we now show that oc cupancy of the class II binding site in the ER regulates class II traf ficking to the Golgi complex, an event that is the locus of the major defect in cells of Ii-deficient mice. These data argue that CLIP occup ies the class II binding site, not to prevent interaction with short p eptides meant for class I, but rather to maintain the structural integ rity of class II molecules that are labile without engaged binding reg ions, and that would also associate with intact proteins in the ER if left unoccupied. By these means, CLIP occupancy of the class II bindin g site promotes effective export of useful class II molecules for endo cytic peptide acquisition.