Klhl6 deficiency impairs transitional B cell survival and differentiation

ABSTRACT: Klhl6 belongs to the KLHL gene family, which is composed of an N-terminal BTB-POZ domain and 4 to 6 Kelch motifs in tandem. Several of these proteins function as adaptors of the Cullin3 E3 ubiquitin ligase complex. Here we report that Klhl6 deficiency induces, as previously described, a two-fold reduction in mature B cells. However, we find that this deficit is centered on the inability of transitional T1 B cells to survive and to progress toward the T2 B cell stage, whereas cells that have passed this step generate normal germinal centers upon a T-dependent immune challenge. Klhl6-deficient T1 B cells showed a two-fold over-expression of genes linked with cell proliferation, including most targets of the APC/C complex, a set of genes whose expression is precisely down-modulated upon culture of splenic transitional B cells in presence of BAFF. These results thus suggest a delay in the differentiation process of Klhl6-deficient B cells between the immature and transitional stage. We further show, in the BL2 Burkitt’s lymphoma cell line, that KLHL6 interacts with Cullin3, but also that it binds to HBXIP/Lamtor5, a protein involved in cell cycle regulation and cytokinesis. Finally, we report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in germinal center B cells in both mice and humans, thus leaving open, whether, in spite of the lack of impact of Klhl6 deficiency on germinal center B cell expansion, mutants could contribute to the oncogenic process.

ORGANISM(S): Mus musculus

SUBMITTER: Nicolas Cagnard 

PROVIDER: E-MTAB-5928 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress