title: Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism.
abstract: Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that coordinates nutrient and growth factor availability with cellular growth, division, and differentiation. Studies examining the roles of mTOR signaling in immune function revealed critical roles for mTOR in regulating T cell differentiation and function. However, few studies have investigated the roles of mTOR in early B cell development. In this study, we found that mTOR is highly activated during the pro- and pre-B stages of mouse B cell development. Conditional disruption of the mTOR coactivating protein Raptor in developing mouse B cells resulted in a developmental block at the pre-B cell stage, with a corresponding lack of peripheral B cells and loss of Ag-specific Ab production. Pre-B cell survival and proliferation were significantly reduced in Raptor-deficient mice. Forced expression of a transgenic BCR or a BclxL transgene on Raptor-deficient B cells failed to rescue B cell development, suggesting that pre-BCR signaling and B cell survival are impaired in a BclxL-independent manner. Raptor-deficient pre-B cells exhibited significant decreases in oxidative phosphorylation and glycolysis, indicating that loss of mTOR signaling in B cells significantly impairs cellular metabolic capacity. Treatment of mice with rapamycin, an allosteric inhibitor of mTOR, recapitulated the early B cell developmental block. Collectively, our data reveal a previously uncharacterized role for mTOR signaling in early B cell development, survival, and metabolism.
authors: Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and.
authors: Terri N
authors: TN
authors: Iwata
authors: Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and.
authors: Julita A
authors: 0000-0002-2253-3364
authors: JA
authors: Ramírez
authors: Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and.
authors: Mark
authors: M
authors: Tsang
authors: Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and.
authors: Heon
authors: H
authors: Park
authors: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors: Daciana H
authors: DH
authors: Margineantu
authors: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors: David M
authors: DM
authors: Hockenbery
authors: Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and biritani@uw.edu.
authors: Brian M
authors: 0000-0003-1903-7850
authors: BM
authors: Iritani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D006019:Glycolysis / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494812:Bcl2l1 protein, mouse; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D014157:Transcription Factors; D051020:bcl-X Protein; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus