Essential requirement for nicastrin in marginal zone and B-1 B cell development

Jin Huk Choi, Jonghee Han, Panayotis C. Theodoropoulos, Xue Zhong, Jianhui Wang, Dawson Medler, Sara Ludwig, Xiaoming Zhan, Xiaohong Li, Miao Tang, Thomas Gallagher, Gang Yu, Bruce Beutler

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4894-4901
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number9
DOIs
StatePublished - Mar 3 2020

Keywords

  • B-1 B cells
  • Marginal zone B cells
  • Nicastrin
  • T cell-independent antibody response

ASJC Scopus subject areas

  • General

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