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.

Exportin-1 (XPO1/CRM1) 在数百种蛋白质的核到细胞质转运中发挥核心作用，并有助于其他细胞过程，例如中心体复制。靶向 XPO1 的小分子可诱导细胞毒性，selinexor 于 2019 年被美国食品和药物管理局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，这对于 NFAT 转录因子的染色质占据以及 T 细胞的适当激活至关重要。此外，我们建立了一类 XPO1 靶向小分子，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 广泛的转录调节作用，这对于 T 细胞激活至关重要，同时还定义了一类新型 XPO1 调节剂，使 XPO1 的治疗靶向能够超越肿瘤学，包括 T 细胞驱动的自身免疫性疾病。