Protein synthesis in plasma cells is regulated by crosstalk between endoplasmic reticulum stress and mTOR signaling.
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.
Institute for Drug Research, The School of Pharmacy, The Hebrew University, Jerusalem, Israel.
Meidan
M
Goldfinger
Miri
M
Shmuel
Sandrine
S
Benhamron
Boaz
B
Tirosh
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D037341:Fumonisins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010950:Plasma Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D017510:Protein Folding / Q000187:drug effects; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000493:pharmacokinetics; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology
C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D037341:Fumonisins; D008070:Lipopolysaccharides; D038601:Ribosomal Protein S6; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; C056933:fumonisin B1; D019284:Thapsigargin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D020123:Sirolimus