2. Academic Validation
  3. 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

  • Nat Chem Biol. 2024 Mar 25. doi: 10.1038/s41589-024-01586-5.
Yi Fan Chen 1 2,  Maryam Ghazala 1 2,  Ryan M Friedrich 1 2,  Brittany A Cordova 3,  Frederick N Petroze 3,  Ramya Srinivasan 1 2,  Kevin C Allan 1,  David F Yan 1 2,  Joel L Sax 1 2,  Kelley Carr 1 2,  Suzanne L Tomchuck 4,  Yuriy Fedorov 1 2,  Alex Y Huang 4,  Amar B Desai 3,  Drew J Adams 5 6
Affiliations

Affiliations

  • 1 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 2 Chemical Biology Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 3 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 4 Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 5 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA. drew.adams@case.edu.
  • 6 Chemical Biology Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA. drew.adams@case.edu.
PMID: 38528120 DOI: 10.1038/s41589-024-01586-5
Abstract

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.

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