V(D)J recombination is a site-specific chromosomal rearrangement process that is responsible for the diversity of T cell receptors (TCRs) and Immunoglobulins (Igs). It is initiated by lymphoid-specific recombinases, RAG1 and RAG2. Although the RAG2 core domain is the minimal region required for V(D)J recombination, the non-core region is also important in rearrangement, and mutations in this region are often related to severe combined immunodeficiency (SCID). However, a complete understanding of the functions of the RAG2 non-core region has not yet been achieved.
A research team led by Prof. Liu Xiaolong from the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences, CAS revealed that the highly conserved RAG2 is essential to protein stability and intact immune system. They found that the zinc finger motif of RAG2 is highly conserved from zebrafish to humans. Using a knock-in mice carrying a zinc finger mutation (C478Y) , they proved that RAG2-C478Y resulted in decreased V(D)J recombination efficiency and serious impairment in T/B cell development due to RAG2 instability. They also showed that other zinc-binding residues in zinc finger module are critical to RAG2 stability. To reinforced the idea that the zinc-binding residues of the RAG2 zinc finger motif are essential for RAG2 stability and V(D)J recombination, they generated a mice harboring a RAG2 non-core region mutation (N474S). N474 is located near C478 but is not zinc-binding, and RAG2-N474S mice exhibit no impairment in either RAG2 stability or T/B cell development.
These findings contribute to the critical functions of the conserved RAG2 non-core region. This work entitled “Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency” was published online in Eur J Immunol on December 22, 2015. This work was supported by grants from Ministry of Science and Technology of China, National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.
CONTACT:
Xiaolong Liu, Principle Investigator
Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai 200031, China.
Tel: 86-21-54921176
Email: liux@sibs.ac.cn
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