The BTB-kelch protein KLHL6 is involved in B-lymphocyte antigen receptor signaling and germinal center formation.
BTB-kelch proteins can elicit diverse biological functions but very little is known about the physiological role of these proteins in vivo. Kelch-like protein 6 (KLHL6) is a BTB-kelch protein with a lymphoid tissue-restricted expression pattern. In the B-lymphocyte lineage, KLHL6 is expressed throughout ontogeny, and KLHL6 expression is strongly upregulated in germinal center (GC) B cells. To analyze the role of KLHL6 in vivo, we have generated mouse mutants of KLHL6. Development of pro- and pre-B cells was normal but numbers of subsequent stages, transitional 1 and 2, and mature B cells were reduced in KLHL6-deficient mice. The antigen-dependent GC reaction was blunted (smaller GCs, reduced B-cell expansion, and reduced memory antibody response) in the absence of KLHL6. Comparison of mutants with global loss of KLHL6 to mutants lacking KLHL6 specifically in B cells demonstrated a B-cell-intrinsic requirement for KLHL6 expression. Finally, B-cell antigen receptor (BCR) cross-linking was less sensitive in KLHL6-deficient B cells compared to wild-type B cells as measured by proliferation, Ca2+ response, and activation of phospholipase Cgamma2. Our results strongly point to a role for KLHL6 in BCR signal transduction and formation of the full germinal center response.
Kroll
Jens
J
Department of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Shi
Xiaozhong
X
Caprioli
Arianna
A
Liu
Hong-Hsing
HH
Waskow
Claudia
C
Lin
Keng-Mean
KM
Miyazaki
Toru
T
Rodewald
Hans-Reimer
HR
Sato
Thomas N
TN
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D022202:Chromosomes, Artificial, Bacterial; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005838:Genotype; D018858:Germinal Center / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D015854:Up-Regulation
D002352:Carrier Proteins; D018076:DNA, Complementary; C489839:Klhl6 protein, mouse; D002118:Calcium