한빛사 논문
Jin Huk Choia,b,1,2, Jonghee Hanc,1, Panayotis C. Theodoropoulosa,d, Xue Zhonga, Jianhui Wanga, Dawson Medlera, Sara Ludwiga, Xiaoming Zhana, Xiaohong Lia, Miao Tanga, Thomas Gallaghera, Gang Yuc, and Bruce Beutlera,2
aCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; cDepartment of Neuroscience, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDepartment of Internal Medicine, Physician Scientist Training Program, Washington University in St. Louis, Barnes Jewish Hospital, St. Louis, MO 63110
1J.H.C. and J.H. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
γ-secretase is an intramembrane protease complex that catalyzes the proteolytic cleavage of amyloid precursor protein and Notch. Impaired γ-secretase function is associated with the development of Alzheimer’s disease and familial acne inversa in humans. In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for defects in adaptive immunity, we identified animals within a single pedigree exhibiting both hypopigmentation of the fur and diminished T cell-independent (TI) antibody responses. The causative mutation was in Ncstn, an essential gene encoding the protein nicastrin (NCSTN), a member of the γ-secretase complex that functions to recruit substrates for proteolysis. The missense mutation severely limits the glycosylation of NCSTN to its mature form and impairs the integrity of the γ-secretase complex as well as its catalytic activity toward its substrate Notch, a critical regulator of B cell and T cell development. Strikingly, however, this missense mutation affects B cell development but not thymocyte or T cell development. The Ncstn allele uncovered in these studies reveals an essential requirement for NCSTN during the type 2 transitional-marginal zone precursor stage and peritoneal B-1 B cell development, the TI antibody response, fur pigmentation, and intestinal homeostasis in mice.
nicastrin, marginal zone B cells, B-1 B cells, T cell-independent antibody response
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