African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.

ABSTRACT: A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevate

SUBMITTER: Singh KS 

PROVIDER: S-EPMC6981190 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature