SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway.
Although the essential role of the adaptor protein SLP-65 in pre-B cell differentiation is established, the molecular mechanism underlying its function is poorly understood. In this study, we uncover a link between SLP-65-dependent signaling and the phosphoinositide-3-OH kinase (PI(3)K)-protein kinase B (PKB)-Foxo pathway. We show that the forkhead box transcription factor Foxo3a promotes light chain rearrangement in pre-B cells. Our data suggest that PKB suppresses light chain recombination by phosphorylating Foxo proteins, whereas reconstitution of SLP-65 function counteracts PKB activation and promotes Foxo3a and Foxo1 activity in pre-B cells. Together, these data illuminate a molecular function of SLP-65 and identify a key role for Foxo proteins in the regulation of light chain recombination, receptor editing and B cell selection.
Herzog
Sebastian
S
Max Planck Institute for Immunobiology, 79108 Freiburg, Germany.
Hug
Eva
E
Meixlsperger
Sonja
S
Paik
Ji-Hye
JH
DePinho
Ronald A
RA
Reth
Michael
M
Jumaa
Hassan
H
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050439:Genes, Immunoglobulin Light Chain / Q000235:genetics*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases