Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells
Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells
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DOI：
10.1182/bloodadvances.2019001139
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发表时间：
2020-05-12
期刊：
影响因子：
7.5
通讯作者：
Hamaguchi, Isao
中科院分区：
文献类型：
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作者：
Ikebe, Emi;Matsuoka, Sahoko;Hamaguchi, Isao
成人T细胞白血病（ATL）患者在接受标准化疗治疗时表现出较差的预后和总生存率，这突出了对人类T细胞白血病病毒1型（HTLV-1）相关疾病开发新型安全有效疗法的持续需求。在这项研究中，我们证明了MK-2048，一种第二代HIV-1整合酶（IN）抑制剂，有效地和选择性地杀死HTLV-1感染的细胞。差异转录组分析显示，MK-2048处理后ATL细胞系中未折叠蛋白反应（UPR）PKR样ER激酶（PERK）信号通路的基因表达水平显著升高。我们还鉴定了葡萄糖调节蛋白78（GRP 78）的显著下调，GRP 78是原代HTLV-1携带者外周血单核细胞（PBMC）的CD 4（+）CADM 1（+）HTLV-1感染细胞群中UPR的主要调节因子（n = 9），表明HTLV-1感染细胞对内质网（ER）应激介导的凋亡高度敏感。MK-2048可有效降低原代HTLV-1携带者PBMC中的前病毒载量（n = 4），但对这些细胞的总数无影响，表明MK-2048不影响HTLV-1未感染PBMC的增殖。MK-2048在HTLV-1感染但非未感染的HTLV-1携带者PBMC细胞中特异性激活ER应激相关促凋亡基因，DNA损伤诱导转录本3蛋白（DDIT 3），也称为C/EBP同源蛋白（CHOP）。我们的研究结果表明，MK-2048通过激活UPR选择性诱导HTLV-1感染的细胞凋亡。HIV IN抑制剂MK-2048在HTLV-1感染细胞中的这种新的调节机制为HTLV-1相关疾病（包括ATL）提供了一个有希望的预防和治疗靶点。
Patients with adult T-cell leukemia (ATL) exhibit a poor prognosis and overall survival rate when treated with standard chemotherapy, highlighting the continued requirement for the development of novel safe and effective therapies for human T-cell leukemia virus type 1 (HTLV-1)-related diseases. In this study, we demonstrated that MK-2048, a second-generation HIV-1 integrase (IN) inhibitor, potently and selectively kills HTLV-1-infected cells. Differential transcriptome profiling revealed significantly elevated levels of gene expression of the unfolded protein response (UPR) PKR-like ER kinase (PERK) signaling pathway in ATL cell lines following MK-2048 treatment. We also identified a significant downregulation in glucose regulated protein 78 (GRP78), a master regulator of the UPR in the CD4(+)CADM1(+) HTLV-1-infected cell population of primary HTLV-1 carrier peripheral blood mononuclear cells (PBMCs) (n = 9), suggesting that HTLV-1-infected cells are hypersensitive to endoplasmic reticulum (ER) stress-mediated apoptosis. MK-2048 efficiently reduced proviral loads in primary HTLV-1 carrier PBMCs (n = 4), but had no effect on the total numbers of these cells, indicating that MK-2048 does not affect the proliferation of HTLV-1-uninfected PBMCs. MK-2048 specifically activated the ER stress-related proapoptotic gene, DNA damage-inducible transcript 3 protein (DDIT3), also known as C/EBP homologous protein (CHOP), in HTLV-1-infected but not uninfected cells of HTLV-1-carrier PBMCs. Our findings demonstrated that MK-2048 selectively induces HTLV-1-infected cell apoptosis via the activation of the UPR. This novel regulatory mechanism of the HIV IN inhibitor MK-2048 in HTLV-1-infected cells provides a promising prophylactic and therapeutic target for HTLV-1-related diseases including ATL.