NCBP1 electrophilic-stress signaling in the nucleus promotes alternatively-spliced S6K1 that dominantly inhibits global translation

Proteome synthesis is profoundly influenced by subcellular stress. However, both the nature of spatiotemporally-restricted cues and the underpinning local responders mediating these cues remain elusive. Unlocking these mechanisms requires an ability to functionally map in living cells locale-specific stress responders and simultaneously interrogate how a localized cue on specific local players contextually impacts proteome synthesis in trans . Here we resolve this prime problem by integrating precision localized electrophile delivery and genetic-code-expansion-based translation reporter tools. Among the four distinct subcellular locales examined, nuclear-targeted stress most prominently inhibits protein translation. We discovered that NCBP1—a nuclear-resident protein with multifaceted roles in eukaryotic mRNA-biogenesis—propagates this nuclear stress signal through a single cysteine (C436) among the 19 conserved, affecting 200 alternative-splicing events across 119 genes differentially-expressed in response to nuclear stress. Global protein-synthesis stall was choreographed by electrophile-labeled NCBP1(C436) triggering the production of alternatively-spliced S6-kinase, which we found to dominantly suppress protein translation.