Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis

• Published in: iScience 2020-10, Vol.23 (10), p.101594, Article 101594
• Main Authors: Olcina, Monica M., Kim, Ryan K., Balanis, Nikolas G., Li, Caiyun Grace, von Eyben, Rie, Graeber, Thomas G., Ricklin, Daniel, Stucki, Manuel, Giaccia, Amato J.
• Format: Article
• Language: English
• Subjects: Cancer; Genetics; Immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101594

The 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 and C4BPA mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific C4BPA mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis in vitro and in vivo. Mechanistically, sensitive C4BPA mutants 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. [Display omitted] •C4BPA mutations 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 signaling Genetics; Immunology; Cancer