摘要：SummaryThe importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner andC4BPAmutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specificC4BPAmutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosisin vitroandin vivo. Mechanistically, sensitiveC4BPAmutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis.Graphical AbstractDisplay OmittedHighlights•C4BPAmutations are associated with improved overall survival in 23 tumor types•C4BPA is found, for the first time, to interact with NF-κB family member RelA•C4BPA expression is regulated in a mutation- and stress-responsive manner•C4BPA has a non-canonical intracellular function in regulating NF-κB signalingGenetics; Immunology; Cancer
