HOIL-1L Interacting Protein (HOIP) Is Essential for CD40 Signaling
HOIL-1L Interacting Protein (HOIP) Is Essential for CD40 Signaling
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DOI：
10.1371/journal.pone.0023061
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发表时间：
2011-08-01
期刊：
影响因子：
3.7
通讯作者：
Rothman, Paul B.
中科院分区：
文献类型：
--
作者：
Hostager, Bruce S.;Kashiwada, Masaki;Rothman, Paul B.
CD 40是一种细胞表面受体，在免疫应答过程中对抗原呈递细胞的活化很重要。在巨噬细胞和树突状细胞中，CD 40与其配体CD 154的结合分别为抗微生物和T细胞介导的免疫应答提供了关键信号。在B细胞中，CD 40信号传导在调节细胞增殖、抗体产生和记忆B细胞发育中具有主要作用。CD 40结合导致受体相关复合物的形成，该复合物介导NF-κ B、应激活化蛋白激酶和其他信号分子的活化。然而，CD 40与这些信号事件的联系机制仅得到部分表征。CD 40信号传导复合物的已知组分包括TNF受体相关因子（TRAF）蛋白家族的成员。我们以前发现TRAF家族成员TRAF 2介导HOIL-1 L相互作用蛋白（HOIP）募集到CD 40的胞质结构域，表明HOIP在CD 40信号通路中发挥作用。为了确定HOIP在CD 40信号传导中的作用，我们使用体细胞基因靶向产生HOIP缺陷的小鼠B细胞系。我们发现，CD 40诱导的CD 80上调和生殖系免疫球蛋白转录的激活在HOIP缺陷细胞中是有缺陷的。我们还发现CD 40介导的NF-κ B和c-Jun激酶的活化受损。在HOIP缺陷的细胞中，I κ B激酶蛋白向CD 40信号复合物的募集是不可检测的，这可能解释了NF-κ B活化的缺陷。HOIP表达的恢复逆转了细胞活化和信号传导的缺陷。这些结果表明HOIP是CD 40信号通路的关键组分。
CD40 is a cell surface receptor important in the activation of antigen-presenting cells during immune responses. In macrophages and dendritic cells, engagement of CD40 by its ligand CD154 provides signals critical for anti-microbial and T cell-mediated immune responses, respectively. In B cells, CD40 signaling has a major role in regulating cell proliferation, antibody production, and memory B cell development. CD40 engagement results in the formation of a receptor-associated complex that mediates activation of NF-kappa B, stress-activated protein kinases, and other signaling molecules. However, the mechanisms that link CD40 to these signaling events have been only partially characterized. Known components of the CD40 signaling complex include members of the TNF receptor-associated factor (TRAF) family of proteins. We previously showed that the TRAF family member TRAF2 mediates recruitment of HOIL-1L-interacting protein (HOIP) to the cytoplasmic domain of CD40, suggesting that HOIP has a role in the CD40 signaling pathway. To determine the role of HOIP in CD40 signaling, we used somatic cell gene targeting to generate mouse B cell lines deficient in HOIP. We found that the CD40-induced upregulation of CD80 and activation of germline immunoglobulin epsilon transcription were defective in HOIP-deficient cells. We also found that the CD40-mediated activation of NF-kappa B and c-Jun kinase was impaired. Recruitment of I kappa B kinase proteins to the CD40 signaling complex was undetectable in HOIP-deficient cells, potentially explaining the defect in NF-kappa B activation. Restoration of HOIP expression reversed the defects in cellular activation and signaling. These results reveal HOIP as a key component of the CD40 signaling pathway.