Juan Chen

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.

Interleukin‐ (IL‐) 38 is an emerging cytokine with multiple functions involved in infection and immunity. However, the potential role of IL‐38 in the host immune response during sepsis remains elusive. Herein, we investigated if macrophages in septic mice express IL‐38, the molecular mechanisms behind its expression, and the downstream effects of its expression. In mouse peritoneal macrophages, lipopolysaccharide (LPS) upregulated IL‐38 and its receptor IL‐36R, and the resulting IL‐38 shifted macrophages from a M1 to M2 phenotype. Moreover, exposure to IL‐38 alone was sufficient to inhibit macrophage apoptosis and LPS‐driven activation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome. These effects were partly abrogated by IL‐38 downregulation. In septic mice, IL‐38 markedly lowered serum concentrations of proinflammatory cytokines and greatly improved survival. Conversely, IL‐38 blockade aggravated their mortality. Collectively, these findings present IL‐38 as a potent immune modulator that restrains the inflammatory response by suppressing macrophage apoptosis and activation of the NLRP3 inflammasome. IL‐38 may help protect organs from sepsis‐related injury.