Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes
Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes
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Cereblon 利用 Myc 依赖性生物能学和 CD8 T 淋巴细胞的活性
DOI：
10.1182/blood.2019003257
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发表时间：
2020-08-13
期刊：
影响因子：
20.3
通讯作者：
Epling-Burnette, Pearlie K.
中科院分区：
文献类型：
--
作者：
Hesterberg, Rebecca S.;Beatty, Matthew S.;Epling-Burnette, Pearlie K.
免疫调节药物，例如沙利度胺和相关化合物，增强了T细胞效应子的功能。 Cereblon（CRBN）是DDB1-果蛋白 - 环E3泛素连接酶复合酶复合物的底物受体，是该药物类别的唯一分子靶标，在该药物类别中，药物诱导的，泛素依赖性的已知“ Neosubstrates”，例如ikaros，ikaros，aiolos，aiolos，aiolos，aiolos，aiolos，aiolos，ayiolos， ，和CK1α，解释其生物学活性。尚不清楚这些CRBN E3连接酶调节化合物是否破坏了CRBN的内源性功能。我们报告CRBN在利用抗原特异性CD8（+）T细胞效应子响应的反馈回路中起作用。具体而言，鼠CD8（+）T细胞中的CRBN缺乏症增强其中心代谢，表现为升高的生物能学，具有超生理学水平的多胺，其次是葡萄糖和氨基酸转运的继发性，以及包括多胺生物合成蛋白质蛋白质蛋白质蛋白素的代谢酶的表达增加脱羧酶。用CRBN调节化合物处理类似地增强了人CD8（+）T细胞的中心代谢。值得注意的是，通过调节化合物或CRBN缺乏对CD8（+）T细胞的代谢控制与主代谢调节剂MYC的增加和持续表达有关。最后，缺陷CRBN的T细胞增强了抗原特异性细胞溶解活性与黑色素瘤肿瘤细胞，离体和体内的肿瘤细胞，并驱动加速且高度侵略性的移植物与宿主病。因此，CRBN的功能可利用CD8（+）T细胞的激活，并且可以通过用药物治疗来利用该表型。
Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1 alpha, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8(+) T-cell effector responses. Specifically, Crbn deficiency in murine CD8(+) T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8(+) T cells. Notably, the metabolic control of CD8(+) T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8(+) T cells, and this phenotype can be exploited by treatment with drugs.