COORDINATION OF IMMUNOGLOBULIN CHAIN FOLDING AND IMMUNOGLOBULIN CHAINASSEMBLY IS ESSENTIAL FOR THE FORMATION OF FUNCTIONAL IGG

The first constant domain (C(H)1) of immunoglobulin heavy (H) chains i s essential for BiP-mediated retention of unassembled H chains in the endoplasmic reticulum (ER). Here, we demonstrated that both wild-type and a mutant gamma chain lacking the C(H)1 domain bind BiP when they a re reduced in vivo. However, only oxidized mutant H chain dimers are r eleased from BiP interaction, whereas oxidized wild-type gamma chain d imers still bind Sip. In light (L) chain-producing cells, some of the mutant H chains accumulate with L chains in ER-derived vesicles and so me are secreted as IgG. Furthermore, only half of the secreted antibod ies bind antigen. We found the same with a mutant gamma chain, in whic h the CHI domain was replaced by a C(H)3 domain. Therefore, we propose that Sip interaction with incompletely folded C(H)1 domains is requir ed to mediate correct assembly of H and L chains.