Role of Activin A-Mediated KAT8 Expression in Regulating Ferroptosis During Mycobacterium tuberculosis Infection

Activin A, a secretory glycoprotein, is up-regulated in patients with tuberculosis, 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 mothers against decapentaplegic homolog (SMAD) 2/3 signaling in Mtb-induced ferroptosis and disease progression. Molecular assays, including chromatin immunoprecipitation and loss-of-function analysis, demonstrated that activin A regulates the expression of KAT8, which in turn regulates levels of heme oxygenase (HO-1). Mechanistically, we identify that KAT8-mediated acetylation of nuclear factor erythroid 2-related factor (NRF2) during Mtb infection enhances its nuclear availability leading to increased HO-1 expression. Finally, using an in vivo mouse model of tuberculosis, we show that the pharmacological inhibition of activin A receptor and KAT8 restricts Mtb burden, limits dissemination and ameliorates tuberculosis pathology. Thus, we report a novel role for activin A in regulating NRF2 localization and outline its potential consequences during tuberculosis.