Activin A mediated KAT8 expression induces ferroptosis during Mycobacterium tuberculosis infection

Abstract Activin A, a secretory glycoprotein, is upregulated in tuberculosis (TB) patients, and its levels are correlated with disease severity. During infection, Mycobacterium tuberculosis (Mtb) induces ferroptosis, an iron-induced mode of cell death, that aids in dissemination and survival. Here, we identify a functional role for activin A and the downstream SMAD2/3 signalling in Mtb-induced ferroptosis and disease progression. Molecular assays, including ChIP and loss-of-function analysis, demonstrated that Activin A regulates the expression of KAT8, which in-turn regulates levels of HO-1. Mechanistically, we identify that KAT8-mediated acetylation of NRF2 during Mtb infection enhances its nuclear availability leading to increased HO-1 expression. Finally, utilizing an in vivo mouse model of TB, we show that the pharmacological inhibition of activin A receptor and KAT8 restricts Mtb burden, limits dissemination and ameliorates TB pathology. Thus, we report a novel role for activin A in regulating NRF2 localisation and outline its potential consequences during TB.