ZDHHC2 promoted antimycobacterial responses by selective autophagic degradation of B-RAF and C-RAF in macrophages.

Abstract

S-Palmitoylation is a reversible post-translational modification involving saturated fatty acid palmitate-to-cysteine linkage in the protein, which guides many aspects of macrophage physiology in health and disease. However, the precise role and underlying mechanisms of palmitoylation in <i>Mycobacterium tuberculosis</i> infection of macrophages remain elusive. Here, we found that <i>M. tuberculosis</i> infection induced the expression of zinc-finger DHHC domain-type palmitoyl-transferases (ZDHHCs), particularly ZDHHC2, in mouse macrophages. Furthermore, ZDHHC2 deficiency in mouse macrophages impaired the immunity against <i>M. tuberculosis</i> and reduced the production of various proinflammatory cytokines. Mechanistic studies revealed the involvement of ZDHHC2 in mediating the palmitoylation of B-RAF and C-RAF, affecting their autophagic degradation and stabilizing protein levels. The increased abundance of B-RAF and C-RAF subsequently increases the activity of the extracellular signal-regulated kinase (ERK) signaling pathway, affecting the survival of <i>M. tuberculosis</i> within macrophages. These findings suggest that ZDHHC2 is a potential target for treating tuberculosis.