Regulation of immunoglobulin synthesis, modification, and trafficking by the unfolded protein response: A quantitative approach

Adi Drori*, Boaz Tirosh

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

4 Scopus citations

Abstract

Plasma cells are professional secretory cells, which function as cellular factories for immunoglobulin synthesis and secretion. Being the sole cell type responsible for antibody secretion they play an essential role in the immune response against a broad spectrum of pathogens. Since plasma cells have a long life span and are able to secrete copious amounts of antibody, their number and repertoire should be tightly regulated. Disruption of their homeostasis may lead to severe diseases, such as immunodeficiency or multiple myeloma. Much of the complications of multiple myeloma are attributed to the antibodies themselves, which accumulate in the bloodstream and lead to kidney and pulmonary insufficiencies. Similar pathologies are common to other plasma cell-related diseases, such as AL amyloidosis and autoimmune diseases, in which Ig molecules accumulate to toxic levels without good means to curtail their production. The process of plasma cell differentiation and maintenance is poorly understood. The discovery that the IRE1/XBP-1 arm of the unfolded protein response (UPR) is necessary to yield full-fledged plasma cells in vivo was a breakthrough in the field. Over the years valuable biochemical information on plasma cell differentiation was obtained by exploring the downstream activities of XBP-1. The most pronounced phenotype of XBP-1 deficiency in plasma cells in vitro is the steep reduction in μ chain synthesis albeit similar levels of its mRNA. Remarkably, the defect is specific to Ig heavy chains as synthesis of other glycoproteins remains normal. Furthermore, when XBP-1 is absent or its mRNA splicing is inhibited the efficiency of protein translocation into the ER is severely impaired. Still, fundamental questions remain unanswered, such as what exactly generates the conditions of endoplasmic reticulum (ER) stress that activates the UPR in the developing plasma cells. Another enigma is how lipid biosynthesis and protein synthesis, both dramatically modulated during differentiation, are coordinated. In this chapter, we will provide detailed methodologies for measurements of Ig synthesis and misinsertion into the ER as readout of ER physiology in the course of plasma cell differentiation.

Original languageAmerican English
Title of host publicationMethods in Enzymology
PublisherAcademic Press Inc.
Pages309-325
Number of pages17
DOIs
StatePublished - 2011

Publication series

NameMethods in Enzymology
Volume491
ISSN (Print)0076-6879

Bibliographical note

Funding Information:
BT is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University (Jerusalem, Israel), and with the Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at the Hebrew University. The authors declare no financial conflict of interest. Research was funded by grants from David R. Bloom Center for Pharmacy, the Rosetrees fund, the Lower Saxony Research Fund, and Israel Science Foundation grant no. 78/09.

Fingerprint

Dive into the research topics of 'Regulation of immunoglobulin synthesis, modification, and trafficking by the unfolded protein response: A quantitative approach'. Together they form a unique fingerprint.

Cite this