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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 9 Pg. 4894-4901 (03 03 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32071239 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Membrane Glycoproteins
• nicastrin protein
• Amyloid Precursor Protein Secretases
• Ethylnitrosourea

Topics

• Adaptive Immunity
• Alzheimer Disease (metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• B-Lymphocyte Subsets (metabolism)
• Cell Membrane (metabolism)
• Ethylnitrosourea (adverse effects)
• Female
• Gene Expression Regulation, Developmental
• Hidradenitis Suppurativa (metabolism)
• Humans
• Hypopigmentation
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mutation
• Pedigree
• T-Lymphocytes (metabolism)
• Transcriptome