Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2

Chi Bun Ko (Corresponding Author), Chris Cheung, Ting-Ting Huang, Ning Chow, Shuqi Zhang, Yanxiang Zhao, Mary Chau, Wing Cheung Chan, Catherine Wong , Daniela Boassa, Sebastien Phan, Mark Ellisman, John Yates III, SongXiao Xu, Zicheng Yu, Yajing Zhang, Rui Zhang, Ling Ling Ng

Research output: Journal article publicationJournal articleAcademic researchpeer-review


NFAT5 is the only known mammalian tonicity-responsive transcription factor with an essential role in cellular adaptation to hypertonic stress. It is also implicated in diverse physiological and pathological processes. NFAT5 activity is tightly regulated by extracellular tonicity, but the underlying mechanisms remain elusive. Here, we demonstrate that NFAT5 enters the nucleus via the nuclear pore complex. We found that NFAT5 utilizes a unique nuclear localization signal (NFAT5-NLS) for nuclear import. siRNA screening revealed that only karyopherin β1 (KPNB1), but not karyopherin α, is responsible for the nuclear import of NFAT5 via direct interaction with the NFAT5-NLS. Proteomics analysis and siRNA screening further revealed that nuclear export of NFAT5 under hypotonicity is driven by exportin-T (XPOT), where the process requires RuvB-like AAA-type ATPase 2 (RUVBL2) as an indispensable chaperone. Our findings have identified an unconventional tonicity-dependent nucleocytoplasmic trafficking pathway for NFAT5 that represents a critical step in orchestrating rapid cellular adaptation to change in extracellular tonicity. These findings offer an opportunity for the development of novel NFAT5 targeting strategies that are potentially useful for the treatment of diseases associated with NFAT5 dysregulation.
Original languageEnglish
Article number10.1242/jcs.259280
Pages (from-to)1-19
Number of pages19
JournalJournal of Cell Science
Issue number13
Publication statusPublished - 12 Jul 2022


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