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Molecular and Cellular Biology, October 2005, p. 8531-8540, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8531-8540.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation

Jens Kroll ,^1,¶, Xiaozhong Shi,^1,¶ Arianna Caprioli,^1,¶ Hong-Hsing Liu,^1,¶ Claudia Waskow,⁴ Keng-Mean Lin,³ Toru Miyazaki,² Hans-Reimer Rodewald,⁴ and Thomas N. Sato^1,5*

Departments of Internal Medicine and Molecular Biology,¹ Center for Immunology,² Alliance for Cellular Signaling and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390,³ Department of Immunology, University of Ulm, D-89070 Ulm, Germany,⁴ Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021⁵

Received 4 December 2005/ Returned for modification 27 January 2005/ Accepted 7 July 2005

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 C2. Our results strongly point to a role for KLHL6 in BCR signal transduction and formation of the full germinal center response.

Supplemental material for this article may be found at http://mcb.asm.org.

^¶ These four authors contributed equally to this work.

Present address: Tumor Biology Center, Freiburg i.Br., Germany.

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