Infection with Mycobacterium tuberculosis orchestrates the PRMT5-dependent methylation of NCOA4 to govern host ferroptosis

Mycobacterium tuberculosis (Mtb) increases availability of free iron resulting in ferroptosis of host macrophages to facilitate its survival and dissemination. A critical factor for elevated levels of labile iron is the overt accumulation of the protein nuclear receptor coactivator 4 (NCOA4), that promotes autophagic degradation of ferritin in a process termed as ferritinophagy. Here, we identify a novel post-translational modification on NCOA4 that is essential for its interaction with ferritin in iron-replete condition of Mtb-infected cells. Specifically, protein arginine methyltransferase 5 (PRMT5), confers a symmetric-dimethylation on NCOA4 that promotes ferritinophagy-mediated ferroptosis. Using loss-of-function studies, we show that PRMT5 is required for lipid peroxidation, bacterial survival, and dissemination in Mtb-infected mice. Also, overexpression of a methylation-deficient mutant of NCOA4 phenocopy depletion of PRMT5 and reduced ferritinophagy in Mtb-infected cells. Furthermore, PRMT5-mediated methylation reduces the nuclear availability of NCOA4 and impairs its co-activatory role to nuclear receptors such as vitamin D3. Thus, our findings uncover the key interaction between NCOA4 and ferritin that regulates ferroptosis and mycobacterial survival during infection. Perturbation of this interaction results in reduced Mtb loads and alleviated disease pathology.