Abstract
Periodic accumulation and degradation of RAG2 (recombination-activating gene 2) protein controls the cell-cycle-dependent V(D)J recombination of lymphocyte antigen receptor genes. Here we show the molecular mechanism of RAG2 degradation. The RAG2 protein is translocated from the nucleus to the cytoplasm and degraded through the ubiquitin/proteasome system. RAG2 translocation is mediated by the Thr-490 phosphorylation of RAG2. Inhibition of this phosphorylation by p27Kip1 stabilizes the RAG2 protein in the nucleus. These results suggest that RAG2 sequestration in the cytoplasm and its subsequent degradation by the ubiquitin/proteasome system upon entering the S phase is an integral part of G0/G1-specific V(D)J recombination.
Highlights
During B and T cell development, the genes encoding the variable region of immunoglobulin (Ig) and the T cell receptor (TCR) are assembled from germ line- variable (V), diversity (D), and joining (J) gene segments by V(D)J recombination [1,2,3]
RAG2 translocation is mediated by the Thr-490 phosphorylation of RAG2. Inhibition of this phosphorylation by p27Kip1 stabilizes the RAG2 protein in the nucleus. These results suggest that RAG2 sequestration in the cytoplasm and its subsequent degradation by the ubiquitin/proteasome system upon entering the S phase is an integral part of G0/G1-specific V(D)J recombination
Ubiquitination of RAG2 Protein—To show that the RAG2 protein is a substrate for ubiquitination, we adopted a highly sensitive in vivo ubiquitination assay system originally developed by Treier et al (Fig. 1B) [18]
Summary
During B and T cell development, the genes encoding the variable region of immunoglobulin (Ig) and the T cell receptor (TCR) are assembled from germ line- variable (V), diversity (D), and joining (J) gene segments by V(D)J recombination [1,2,3]. The RAG2 protein is translocated from the nucleus to the cytoplasm and degraded through the ubiquitin/proteasome system. The phosphorylated p27Kip1 is translocated from the nucleus to the cytoplasm, associated with the SCF (Skp1/cullin1/F-box protein) E3 ubiquitin-ligase complex through this CDK-phosphorylation site, ubiquitinated and degraded by the 26S proteasome, which promotes the cell-cycle transition from G1 to S.
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