The BTB-kelch protein KLHL6 is involved in B-lymphocyte antigen receptor signaling and germinal center formation

Jens Kroll, Xiaozhong Shi, Arianna Caprioli, Hong Hsing Liu, Claudia Waskow, Keng Mean Lin, Toru Miyazaki, Hans Reimer Rodewald, Thomas N. Sato

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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 Cγ2. Our results strongly point to a role for KLHL6 in BCR signal transduction and formation of the full germinal center response.

Original languageEnglish (US)
Pages (from-to)8531-8540
Number of pages10
JournalMolecular and cellular biology
Volume25
Issue number19
DOIs
StatePublished - Oct 2005

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