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

The first constant domain (C(H)1) of immunoglobulin heavy (H) chains is 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 are reduced in vivo. However, only oxidized mutant H chain dimers are released from BiP interaction, whereas oxidized wild-type gamma chain dimers still bind Sip. In light (L) chain-producing cells, some of the mutant H chains accumulate with L chains in ER-derived vesicles and some are secreted as IgG. Furthermore, only half of the secreted antibodies bind antigen. We found the same with a mutant gamma chain, in which 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 required to mediate correct assembly of H and L chains.