HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells
HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells
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HSP70-Hrd1 轴排除了 N 端错误折叠的 Blimp-1 在淋巴瘤细胞中的抑癌潜力
DOI：
10.1038/s41467-017-00476-w
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发表时间：
2017-08-25
影响因子：
16.6
通讯作者：
Zhu, Jiang
中科院分区：
文献类型：
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作者：
Wang, Wen-Fang;Yan, Li;Zhu, Jiang
B淋巴细胞诱导成熟蛋白-1（Blimp-1）确保B细胞分化为浆细胞阶段，并且其不稳定性在活化的B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）的某些侵袭性病例中构成关键的致癌因素。然而，潜在的降解机制及其可能的治疗相关性仍未探索。在这里，我们发现ABC-DLBCL中的N-末端错误折叠突变使Blimp-1蛋白对蛋白酶体介导的降解敏感，但保留了其转录调节活性。从机制上讲，而野生型Blimp-1代谢是通过PML介导的类小泛素化在细胞核中触发的，淋巴瘤相关突变体的降解是通过颠覆Hrd 1介导的细胞质螯合和泛素化来加速的。筛选实验确定了热休克蛋白70（HSP 70），选择Blimp-1突变体的Hrd 1协会，和HSP 70抑制恢复其核积累和抑癌活性，而不破坏正常的B细胞成熟。因此，HSP 70-Hrd 1轴代表了恢复不稳定淋巴瘤相关Blimp-1突变体的抑癌活性的潜在治疗靶点。
B lymphocyte-induced maturation protein-1 (Blimp-1) ensures B-cell differentiation into the plasma cell stage, and its instability constitutes a crucial oncogenic element in certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). However, the underlying degradation mechanisms and their possible therapeutic relevance remain unexplored. Here, we show that N-terminal misfolding mutations in ABC-DLBCL render Blimp-1 protein susceptible to proteasome-mediated degradation but spare its transcription-regulating activity. Mechanistically, whereas wild-type Blimp-1 metabolism is triggered in the nucleus through PML-mediated sumoylation, the degradation of lymphoma-associated mutants is accelerated by subversion of this pathway to Hrd1-mediated cytoplasmic sequestration and ubiquitination. Screening experiments identifies the heat shock protein 70 (HSP70) that selects Blimp-1 mutants for Hrd1 association, and HSP70 inhibition restores their nuclear accumulation and oncorepressor activities without disrupting normal B-cell maturation. Therefore, HSP70-Hrd1 axis represents a potential therapeutic target for restoring the oncorepressor activity of unstable lymphoma-associated Blimp-1 mutants.