Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.
Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.
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DOI：
10.1038/s41589-024-01586-5
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发表时间：
2024-03
影响因子：
14.8
通讯作者：
Yi Fan Chen;Maryam Ghazala;Ryan M. Friedrich;Brittany A. Cordova;Frederick N Petroze;Ramya Srinivasan;Kevin C Allan;David F Yan;J. Sax;Kelley Carr;Suzanne L. Tomchuck;Yuriy Fedorov;Alex Y Huang;Amar B. Desai;Drew J Adams
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作者：
Yi Fan Chen;Maryam Ghazala;Ryan M. Friedrich;Brittany A. Cordova;Frederick N Petroze;Ramya Srinivasan;Kevin C Allan;David F Yan;J. Sax;Kelley Carr;Suzanne L. Tomchuck;Yuriy Fedorov;Alex Y Huang;Amar B. Desai;Drew J Adams
输出蛋白-1 （XPO1/CRM1）在数百种蛋白质的核到胞质运输中起核心作用，并参与其他细胞过程，如中心体复制。针对XPO1的小分子诱导细胞毒性，selinexor于2019年被美国食品和药物管理局（fda）批准作为复发性多发性骨髓瘤的癌症化疗药物。在这里，我们描述了XPO1的细胞类型依赖性染色质结合功能，该功能对于NFAT转录因子的染色质占用和T细胞的适当激活至关重要。此外，我们建立了一类靶向XPO1的小分子，能够破坏XPO1的染色质结合，而不干扰核输出或诱导细胞毒性。这项工作定义了XPO1广泛的转录调控作用，这对T细胞激活和一类新的XPO1调节剂至关重要，使XPO1的治疗靶向性超越肿瘤，包括T细胞驱动的自身免疫性疾病。
Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.