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

Eur J Immunol. 2011 Feb;41(2):491-502. doi: 10.1002/eji.201040677. Epub 2010 Dec 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Antibody Formation
  • Apoptosis / immunology
  • B-Lymphocyte Subsets / drug effects
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cell Differentiation / physiology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fumonisins / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Plasma Cells / cytology
  • Plasma Cells / drug effects
  • Plasma Cells / metabolism*
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / physiology*
  • Protein Folding / drug effects
  • Ribosomal Protein S6 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Sirolimus / pharmacokinetics
  • Stress, Physiological / drug effects
  • Stress, Physiological / physiology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Thapsigargin / pharmacology
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Tunicamycin / pharmacology

Substances

  • Atf4 protein, mouse
  • Eukaryotic Initiation Factor-2
  • Fumonisins
  • Lipopolysaccharides
  • Ribosomal Protein S6
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Tunicamycin
  • Activating Transcription Factor 4
  • fumonisin B1
  • Thapsigargin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Phosphoprotein Phosphatases
  • Sirolimus