The major objective of this proposed project is to analyze the mechanisms involved in the intracellular transport of immunoglobulin (Ig) proteins. We are primarily interested in determining how Ig proteins are selectively transported from their sites of synthesis through cellular compartments and targeted to their final fate as either secreted, membrane-bound or intracellularly degraded proteins. During the life cycle of a B lymphocyte, the biosynthesis of immunoglobulin proteins is developmentally regulated. The availability of B cell lines representing each stage of development makes this cell lineage an excellent model for studying the mechanisms involved in such regulatory processes. Specifically, we will concentrate on the role that the recently discovered heavy chain binding protein (BP) and light chains play (i) in directing the transport of immunoglobulin between intracellular organelles and (ii) in directing the disparate pathways of secreted and membrane-bound Ig in B cells. Proteins destined for secretion or surface expression must be distinguished from constitutive cellular components and selectively transported from the endoplasmic reticulum (ER) to the Golgi. We propose that BP plays a role in preventing Ig molecules, destined for the secretory pathway, from exiting the ER until assembly is complete. We have found BP to be present in all cell types examined, regardless of species of origin. Therefore, although this protein appears to play an important role in the metabolism of immunoglobulin heavy chains, it may also play a more general role in the intracellular transport of proteins. To determine its role in other cell types, we will examine the association of BP with mutant viral proteins which are defective in transport and compare them to wild-type viral glycoproteins. We will also exploit the ability of several agents which inhibit or block the transport of certain proteins to prolong their association with BP and thereby increase our chances of detecting it.
| Hendershot, L M; Ting, J; Lee, A S (1988) Identity of the immunoglobulin heavy-chain-binding protein with the 78,000-dalton glucose-regulated protein and the role of posttranslational modifications in its binding function. Mol Cell Biol 8:4250-6 |
