title: mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion.
abstract: Plasma cells (PCs) are responsible for the secretion of antibodies. The development of fully functional PCs relies on the activation of the inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP-1) arm of the unfolded protein response (UPR). XBP-1-deficient PCs secrete antibodies poorly and exhibit distensions of the endoplasmic reticulum (ER). The kinase mammalian target of rapamycin (mTOR) promotes anabolic activities and is negatively regulated by the tuberous sclerosis complex (TSC). Deletion of TSC1 renders mTOR hyperactive. To explore the relationship between mTOR and the UPR in PC development and function, mice with conditional deletions of XBP-1 and/or TSC1 in their B cell lineage were generated. Deletion of TSC1 enhanced Ig synthesis and promoted differentiation into PCs independently of XBP-1, as evidenced by comparison of TSC1/XBP-1 double-knockout (DKO) PCs to XBP-1 knockout (KO) PCs. The typical morphological abnormalities of the ER in XBP-1 KO PCs were alleviated in the DKO PCs. Expression profiling identified the glycoprotein Ly6C as an mTOR target. Ly6C expression contributed to the enhanced Ig secretion from DKO PCs. Our data reveal a functional overlap between mTOR and the UPR in promoting PC development. In addition to the classical mTOR role in promoting protein synthesis, the mechanism entails transcription regulation of accessory molecules, such as Ly6C.
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Benhamron
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shakti P
authors.initials: SP
authors.lastname: Pattanayak
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel boazt@ekmd.huji.ac.il.
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007070:Immunoglobulin A / Q000378:metabolism; D007136:Immunoglobulins / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation; D000071701:Regulatory Factor X Transcription Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D018941:Antigens, CD19; D000950:Antigens, Ly; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D007136:Immunoglobulins; C494192:Ly-6C antigen, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D058570:TOR Serine-Threonine Kinases