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Full text release has been delayed at the author's request until May 17, 2026

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Beyond Nuclear Export: Expanding the Biology and Chemical Biology of Exportin-1

Chen, Yi Fan
http://orcid.org/0000-0002-7757-4462
http://rave.ohiolink.edu/etdc/view?acc_num=case171231823947012

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Genetics.
Exportin-1 (XPO1) is an essential regulator of cellular nuclear export that traffics hundreds of cargo proteins from the nucleus into the cytoplasm. Nearly three decades of research led to a detailed understanding of the mechanisms underlying XPO1-mediated transport, and this knowledge generated many XPO1-targeting small molecule probes that validated the therapeutic potential of drugging nucleocytoplasmic trafficking. More recently, growing evidence has implicated XPO1 in other functions, including in the coordination of mitotic events, regulation of gene transcription, and formation of biomolecular condensates. These functions operate independently of nuclear export and implicate XPO1 as a broad regulator of many cellular functions. In this work, we demonstrate that many structural classes of electrophilic small molecules target XPO1 at cysteine 528 to suppress T cell activation. In contrast to known cytotoxic XPO1 modulators such as Leptomycin B and the FDA-approved Selinexor, we identify a new class of “Selective Inhibitors of Transcriptional Activation” (SITAs) that display potent inhibition of T cell function with minimal impacts on XPO1-mediated nuclear export, mitotic regulation, and cell viability. To assess how SITAs suppress T cell activation despite their muted effects on nuclear export, we provide evidence that XPO1 scaffolds transcription factors of the NF-κB, AP-1, and NFAT families during T cell activation. SITAs selectively disrupt XPO1 occupancy at euchromatic regions to indirectly abrogate the chromatin localization of NFAT, thereby suppressing T cell activation without affecting cell viability. Beyond the transcription factors that are critical for T cell function, we further demonstrate that the p300 histone acetyltransferase shares many chromatin occupancy sites with XPO1. Targeted modulation of XPO1 by SITAs or small molecule degraders indirectly suppresses p300 chromatin binding and activity, providing a potential mechanistic link between XPO1 and global chromatin accessibility. Our work establishes XPO1 as a bona fide chromatin factor that is essential for the localization of many epigenetic regulators. We propose that new classes of small molecule XPO1 probes with divergent cellular activity profiles can unravel the non-canonical functions of XPO1 to expand its rich underlying biology and therapeutic opportunities beyond nuclear export.
Drew Adams (Advisor)
George Dubyak (Committee Member)
Anthony Wynshaw-Boris (Committee Member)
Paul Tesar (Committee Chair)
236 p.
Biology; Biomedical Research; Cellular Biology; Chemistry; Immunology; Molecular Biology; Organic Chemistry; Pharmacology
XPO1, CRM1, nuclear export, chromatin scaffolding, small molecules, chemical biology, epigenomics

Recommended Citations

Citations

  • Chen, Y. F. (2024). Beyond Nuclear Export: Expanding the Biology and Chemical Biology of Exportin-1 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case171231823947012

    APA Style (7th edition)

  • Chen, Yi Fan. Beyond Nuclear Export: Expanding the Biology and Chemical Biology of Exportin-1 . 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case171231823947012.

    MLA Style (8th edition)

  • Chen, Yi Fan. "Beyond Nuclear Export: Expanding the Biology and Chemical Biology of Exportin-1 ." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case171231823947012

    Chicago Manual of Style (17th edition)

case171231823947012
© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.