NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation

Journal article

Subcellular stress profoundly influences protein synthesis. However, both the nature of spatiotemporally restricted chemical cues and local protein responders to these cues remain elusive. Unlocking these mechanisms requires the ability to functionally map in living systems locale-specific stress-responder proteins and interrogate how chemical modification of each responder impacts proteome synthesis. We resolved this problem by integrating precision localized electrophile generation and genetic code expansion tools. Upon examination of four distinct subcellular locales, only nuclear-targeted electrophile stress stalled translation. We discovered that NCBP1—a nuclearresident protein with multifaceted roles in eukaryotic mRNA-biogenesis—propagated this nuclear stress signal through a single cysteine (C436) from among its 19 conserved cysteines. This NCBP1(C436)-specific modification elicited alternative splicing of >250 genes. Mechanistically, global protein-synthesis stall was choreographed by impaired association between electrophile-modified NCBP1(C436) and SF3A1, an essential component of spliceosome, triggering the production of alternatively-spliced S6-kinase, whose expression was sufficient to dominantly inhibit protein translation.

Authors: Chang, DC; Assari, M; Suwathep, C; Sappakhaw, K; Uttamapinant, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Chemical Biology
• Publication date: 2026-02-10
• Acceptance date: 2025-12-18
• DOI: 10.1038/s41589-025-02135-4
• EISSN: 1552-4469
• ISSN: 1552-4450
• Language: English