Prolonged endoplasmic reticulum stress promotes mislocalization of immunoglobulins to the cytoplasm

Adi Drori, Shahram Misaghi, Joseph Haimovich, Martin Messerle, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Signal peptide-dependent insertion of newly synthesized proteins into the endoplasmic reticulum (ER) is a multi-step process, whose fidelity varies with the identity of the protein and the cell type. ER translocation of prions is sensitive to conditions of acute ER stress in a manner that pre-emptively prevents their aggregation and proteo-toxicity. While this has been documented for extreme ER stress conditions and for a special type of proteins, the impact of chronic ER stress on protein translocation in general has not been well characterized.The unfolded protein response (UPR) is a cytoprotective signaling pathway activated by ER stress. The transcription factor X-box-binding protein 1 (XBP-1) is a key element of the mammalian UPR, which is activated in response to ER stress. Deletion of XBP-1 generates constitutive chronic ER stress conditions. Chronic ER stress can also be produced pharmacologically, for example by prolonged treatment with proteasome inhibitors, which abrogates XBP-1 activation.We tested the impact of chronic ER stress on protein insertion into the ER with special emphasis on antibody secreting cells (ASCs), as these cells cope physiologically with prolonged stress conditions. We show that XBP-1 in plasmablasts and fibroblasts controls the ER translocation of US2, a viral-encoded protein with a priori poor insertion efficiency. Using monoclonal antibodies that preferentially recognize ER-mis-inserted μ Ig chains we demonstrate that prolonged treatment of plasmablasts with proteasome inhibitors, as well as deletion of XBP-1, impaired the translocation of μ chains to the ER. Our data suggest that ASCs under prolonged ER stress conditions endure cytoplasmic mislocalization of Ig proteins. This mislocalization may further explain the exquisite sensitivity of multiple myeloma to proteasome inhibitors.

Original languageAmerican English
Pages (from-to)1719-1727
Number of pages9
JournalMolecular Immunology
Issue number9
StatePublished - May 2010

Bibliographical note

Funding Information:
We would like to thank Dr. Hidde Ploegh for valuable reagents and support in generating the monoclonal antibodies. 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. Research was funded by grants from David R. Bloom Center For Pharmacy (BT), The Rosetrees Fund (BT), the Lower Saxony Research Fund (BT and MM) and Israel Science Foundation grant no. 78/09 (BT).


  • Antibodies
  • B cells
  • Cell differentiation
  • Endoplasmic reticulum
  • Unfolded protein response


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