Department of Microbiology & Immunology, University of Iowa, Iowa City, IA, USA.
Immunology Graduate Program, University of Iowa, Iowa City, IA, USA.
Sci Rep. 2019 Sep 9;9(1):12884. doi: 10.1038/s41598-019-49390-9.
TRAF3 is a versatile intracellular adapter protein with multiple context-specific roles. Uniquely in B cells, TRAF3 deficiency enhances survival and increases the risk of transformation, as loss of TRAF3 is observed in several types of B cell cancers. Here, we report a new mechanism for TRAF3 in the restraint of B cell survival. We found that TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines. The increase in Pim2 was independent of NF-κB2 activation but was ameliorated with inhibition of STAT3 expression or function. TRAF3 deficiency also led to a Pim2-dependent increase in c-Myc protein levels and was associated with reduced c-Myc ubiquitination. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. Interestingly, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibition-induced cell death. Combination treatment of TRAF3-deficient B cells and B cell tumor lines with c-Myc inhibitors enhanced their sensitivity to Pim inhibition, suggesting a possible therapeutic strategy. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for treatment of B cell malignancies.
TRAF3 是一种多功能的细胞内衔接蛋白，具有多种特定于上下文的作用。在 B 细胞中独一无二的是，TRAF3 缺乏会增强存活并增加转化的风险，因为几种类型的 B 细胞癌中都观察到 TRAF3 的缺失。在这里，我们报告了 TRAF3 抑制 B 细胞存活的一种新机制。我们发现，TRAF3 缺乏与在小鼠原代 B 细胞和人恶性 B 细胞系中诱导生存激酶 Pim2 的表达有关。Pim2 的增加独立于 NF-κB2 的激活，但可通过抑制 STAT3 的表达或功能得到改善。TRAF3 缺乏还导致 Pim2 依赖性 c-Myc 蛋白水平增加，并与 c-Myc 泛素化减少有关。TRAF3 缺陷的原代 B 细胞对 Pim 抑制剂 SGI-1776 和 TP-3654 诱导的细胞死亡的敏感性降低。有趣的是，TRAF3 表达水平低的人恶性 B 细胞系对 Pim 抑制诱导的细胞死亡更为敏感。用 c-Myc 抑制剂联合治疗 TRAF3 缺陷的 B 细胞和 B 细胞肿瘤系增强了它们对 Pim 抑制的敏感性，提示了一种可能的治疗策略。因此，TRAF3 抑制了 Pim2 介导的 B 细胞存活轴，这可能是治疗 B 细胞恶性肿瘤的潜在靶点。
