Interactome of histone locus body scaffold protein NPAT

Importins could inhibit the condensation of RNA-binding proteins, while it is proposed that exportins could not elicit a similar function. Here, we identified exportin CRM1 binds nuclear protein NPAT, which initiates and maintains the formation of histone locus body (HLB), a membrane-less nuclear body determining histone transcription. CRM1 drives the nuclear export of NPAT by targeting a cryptical nuclear export signal (NES) motif 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 to suppress 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.