Activin A mediated KAT8 expression induces ferroptosis during Mycobacterium tuberculosis infection

Abstract

Activin A, a secretory glycoprotein, has been shown to be upregulated in TB patients, and its levels are correlated with disease severity. Here, we identify a functional role for activin A and the downstream SMAD2/3 signalling in Mtb pathogenesis and dissemination. Molecular assays, including ChIP and loss-of-function analysis, demonstrated that Activin A regulates the expression of lysine acetyltransferase (KAT) 8, which in turn regulates HO-1 levels and Mtb-induced ferroptosis. Mechanistically, we identify KAT8-mediated acetylation of NRF2 during Mtb infection, leading to enhanced nuclear availability of the transcription factor and increased expression of HO-1. Finally, utilizing an in vivo mouse model of TB, we show that the pharmacological inhibition of activin A receptor and KAT8 restricts Mtb burden, 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.