Nup42 safeguards heat-induced mRNAs from nuclear condensation to support chaperone synthesis.

Cells exposed to acute stress selectively express stress-adaptive genes while repressing growth-related genes. Upon heat shock, most pre-existing mRNAs localize to translationally repressed biomolecular condensates. How heat-induced mRNAs evade condensation and remain translationally competent remains unclear. Here, we show that ribosomal protein-coding transcripts preferentially accumulate in condensates during heat shock, whereas heat-induced chaperone mRNAs are selectively excluded and preferentially translated. Using a whole-genome CRISPRi screening platform, Fractionation of Reporter-Seq (FRep-Seq), we identify the nucleoporin Nup42 as the strongest suppressor of heat-induced mRNA condensation. Loss of Nup42 triggers temperature- and transcription-dependent nuclear condensation of chaperone mRNAs, which are exported but remain translationally incompetent, leading to impaired chaperone production and thermosensitivity. Co-transcriptional mRNP packaging is a critical determinant of condensation in the absence of Nup42. Together, our findings reveal a nuclear, translation-independent layer of mRNP solubility control that enables heat shock gene expression.