Brucella abortus infection exploits ZDHHC3-mediated STAT3 palmitoylation to regulate host responses and promote persistence.

Brucella abortus, an intracellular bacterium, employs intricate mechanisms to manipulate host signaling for persistence. This study investigates the role of STAT3 palmitoylation in B. abortus-infected macrophages. We demonstrate that B. abortus infection induces STAT3 palmitoylation, which is critical for its membrane recruitment. Among zinc finger DHHC-type palmitoyl acyltransferases (ZDHHC) family members, ZDHHC3 specifically mediates STAT3 palmitoylation in infected macrophages. ZDHHC3-induced STAT3 palmitoylation promotes STAT3 phosphorylation at Y705, independently of IL-6. Functionally, ZDHHC3 suppresses pro-inflammatory cytokines (IL-1β, TNF-α) and nitric oxide (NO) production, while increasing anti-inflammatory IL-10, thereby enhancing intracellular B. abortus survival. In vivo, ZDHHC3 mRNA is upregulated in splenic macrophages during infection, and 2-bromopalmitate (2BP) treatment reduces bacterial burden in mice, associated with elevated TNF-α and IFN-γ. Additionally, ZDHHC3 inhibits macrophage apoptosis (via regulating Bax and Bcl-2), limiting bacterial egress from apoptotic cells. These findings identify ZDHHC3-mediated STAT3 palmitoylation as one of the key regulatory mechanism in B. abortus infection, linking lipid modification to STAT3 activation, inflammation, apoptosis, and bacterial persistence.