CRM1 inhibits NPAT condensation and histone locus body formation via a competitive occupation strategy

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Abstract
Importins could inhibit the condensation of RNA-binding proteins, while it remains unknown whether exportins elicit a similar function. Here, we identified that exportin CRM1 binds to the nuclear protein NPAT, which initiates and maintains the formation of the histone locus body (HLB), a membraneless nuclear body regulating histone transcription. CRM1 drives the nuclear export of NPAT by targeting a nuclear export signal (NES) within the LisH domain. The LisH domain contributes to NPAT condensation by mediating its self-association. Mechanistically, CRM1 competitively occupies the self-association sites in the NES motif, thereby suppressing NPAT condensation. In contrast, the two recurrent CRM1 E571K and E571G mutants could not regulate NPAT condensation and HLB remodeling due to their impaired binding to the NES of NPAT. Based on the “competitive occupation” model, we designed a LisH domain–derived short peptide that competes with homotypic intermolecular interactions of NPAT to perturb HLB formation. Our findings reveal that exportin regulates nuclear protein condensation via a competitive occupation strategy.
Funding Information
  • National Natural Science Foundation of China (T2121004)
  • National Natural Science Foundation of China (32070821)
  • National Natural Science Foundation of China (32270720)
  • National Natural Science Foundation of China (32100671)
  • National Key Research and Development Program of China (2021YFA1100500)
  • Science and Technology Commission of Zhejiang Province (2022R52040)
  • Key R&D Program of Zhejiang (2024SSYS0027)
  • Fundamental Research Funds for the Central Universities (226202400061)
  • Fundamental Research Funds for the Central Universities (226202300100)
  • China Postdoctoral Science Foundation (2021M702848)
  • National Natural Science Foundation of China (T2121004)
  • National Natural Science Foundation of China (32070821)
  • National Natural Science Foundation of China (32270720)
  • National Natural Science Foundation of China (32100671)
  • National Key Research and Development Program of China (2021YFA1100500)
  • Science and Technology Commission of Zhejiang Province (2022R52040)
  • Key R&D Program of Zhejiang (2024SSYS0027)
  • Fundamental Research Funds for the Central Universities (226202400061)
  • Fundamental Research Funds for the Central Universities (226202300100)
  • China Postdoctoral Science Foundation (2021M702848)

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