PUBLICATION
Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency
- Authors
- Xu, K., Liu, H., Shi, Z., Song, G., Zhu, X., Jiang, Y., Zhou, Z., Liu, X.
- ID
- ZDB-PUB-151223-4
- Date
- 2016
- Source
- European journal of immunology 46(4): 1011-9 (Journal)
- Registered Authors
- Keywords
- Animal models, Cell differentiation, Knout out mice, V(D)J recombination, severe combined immunodeficiency (SCID)
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- B-Lymphocytes/cytology
- B-Lymphocytes/immunology*
- Base Sequence
- Cells, Cultured
- Conserved Sequence/genetics
- DNA-Binding Proteins/genetics*
- Gene Knockout Techniques
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Sequence Data
- Protein Stability
- Sequence Alignment
- Severe Combined Immunodeficiency/genetics*
- Severe Combined Immunodeficiency/immunology
- T-Lymphocytes/cytology
- T-Lymphocytes/immunology*
- V(D)J Recombination/genetics
- Zinc Fingers/genetics*
- PubMed
- 26692406 Full text @ Eur. J. Immunol.
Citation
Xu, K., Liu, H., Shi, Z., Song, G., Zhu, X., Jiang, Y., Zhou, Z., Liu, X. (2016) Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency. European journal of immunology. 46(4):1011-9.
Abstract
Although the RAG2 core domain is the minimal region required for V(D)J recombination, the non-core region also plays important roles in the regulation of recombination, and mutations in this region are often related to severe combined immunodeficiency (SCID). A complete understanding of the functions of the RAG2 non-core region and the potential contributions of its individual residues has not yet been achieved. Here, we show that the zinc finger module within the non-core region of RAG2 is indispensable for maintaining the stability of the RAG2 protein. The zinc finger motif in the non-core region of RAG2 is highly conserved from zebrafish to humans. Knock-in mice carrying a zinc finger mutation (C478Y) exhibit decreased V(D)J recombination efficiency and serious impairment in T/B cell development due to RAG2 instability. Further studies also reveal the importance of the zinc finger module for RAG2 stability. Moreover, mice harboring a RAG2 non-core region mutation (N474S), which is located near C478 but is not zinc-binding, exhibit no impairment in either RAG2 stability or T/B cell development. Taken together, our findings contribute to defining critical functions of the RAG2 zinc finger motif and provide insights into the relationships between the mutations within this motif and immunodeficiency diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping