A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination

Ferroptosis is an iron-dependent programmed cell death caused by lipid peroxidation. Emerging evidence suggests several pathogens manipulate ferroptosis as a way for pathogen propagation, but the underlying mechanisms remain largely elusive. Here, we report that PtpA, secreted by intracellular pathogen Mycobacterium tuberculosis (Mtb), is a ferroptosis inducer during infection. Mechanistically, Mtb PtpA entries into the nucleus through the RaDAR pathway depending on the conserved cysteine 11 site, but not canonical ARs motif. Then, PtpA functions as an adaptor to increase the affinity between protein arginine methyltransferase 6 (PRMT6) with its substrate histone H3, thus promoting the asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a), leading to repression of GPX4 gene expression and the ensuing ferroptosis. Accordingly, disrupting nucleus entry site or PRMT6-interacting motif of PtpA markedly eliminates the PtpA-induced ferroptosis in host cells. These findings find a new motif involved in intracellular pathogens effectors for entering host nucleus, and reveal an unrecognized regulatory role of PtpA as an activator of methyltransferases PRMT6 to promote ferroptosis in host nuclear, providing fresh insights into the mechanism of Mtb-induced cell death. U937 cells infected with BCG or ptpA KO BCG at MOI of 10 for 24 h, and then were exacted RNA for RNA sequencing