Tusche Michael W, Ward Lesley A, Vu Frances, McCarthy Doug, Quintela-Fandino Miguel, Ruland Jurgen, Gommerman Jennifer L, Mak Tak W
Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
J Exp Med. 2009 Nov 23;206(12):2671-83. doi: 10.1084/jem.20091802. Epub 2009 Nov 16.
B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-kappaB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
肿瘤坏死因子家族的B细胞活化因子（BAFF）可激活非经典核因子κB（NF-κB）异二聚体，从而促进B细胞存活。我们发现，虽然MALT1在很大程度上对于B细胞受体下游的经典NF-κB信号传导并非必需，但MALT1的缺失会导致BAFF诱导的B220(+) B细胞中NF-κB2（p100）磷酸化受损、p100降解受损以及RelB核转位受损。这与体外BAFF刺激下MALT1(-/-)边缘区（MZ）B细胞而非滤泡B细胞的存活受损相对应。MALT1(-/-) MZ B细胞还表达更高水平的TRAF3，TRAF3是已知的BAFF受体介导信号传导的负调节因子，并且发现TRAF3与MALT1相互作用。此外，发现与BAFF过表达相关的表型，包括MZ B细胞数量增加、血清免疫球蛋白滴度升高和生发中心自发形成，都依赖于B细胞内源性MALT1的表达。我们的结果证明了MALT1在BAFF介导的信号转导所诱导的生物学结果中的新作用。
