Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling

Meidan Goldfinger, Miri Shmuel, Sandrine Benhamron, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Plasma cells (PCs) secrete copious levels of immunoglobulins. To achieve this, their endoplasmic reticulum (ER) undergoes expansion in a process that requires continuous ER stress and activation of the unfolded protein response. It is important that protein synthesis, the driver of ER stress, is regulated in a manner that does not induce apoptosis. We followed protein synthesis in murine splenic B cells activated in vitro with LPS. Total protein synthesis levels increased and then steeply decreased when the cells acquired a secretory phenotype. We explored the involvement of two mechanisms in controlling protein synthesis levels, namely ER stress-mediated phosphorylation of eukaryote initiation factor 2α (eIF2α) and the mammalian target of rapamycin (mTOR) pathway, which attenuate or activate mRNA translation, respectively. We show that induction of ER stress in activated B cells counter-intuitively led to dephosphorylation of eIF2α. Despite the reduction in phosphorylated eIF2α, expression of activating transcription factor 4, an effector of hyper eIF2α phosphorylation, was induced. In addition, ER stress attenuated the mTOR pathway, which ultimately reduced protein synthesis. Finally, B cells engineered to overactivate the mTOR pathway exhibited higher apoptosis in the course of LPS stimulation. We conclude that protein synthesis in PCs is controlled by an ER stress-mediated mTOR regulation, which is needed for optimal cell viability.

Original languageAmerican English
Pages (from-to)491-502
Number of pages12
JournalEuropean Journal of Immunology
Volume41
Issue number2
DOIs
StatePublished - Feb 2011

Keywords

  • ER stress
  • MTOR
  • Plasma cells
  • Unfolded protein response

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