ZDHHC2 Promoted Antimycobacterial Responses by Selective Autophagic Degradation of B-RAF and C-RAF in Macrophages

Overview

Journal Sci Adv

Date 2025 Jan 24

PMID 39854453

Authors

Junli Sheng

Xiaolong You

Dingnai Nie

Yuling Fu

Qiao Ling

Xiaodan Yang

Yitian Chen

Li Ma

Shengfeng Hu

Affiliations

Soon will be listed here.

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 infection of macrophages remain elusive. Here, we found that 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 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 within macrophages. These findings suggest that ZDHHC2 is a potential target for treating tuberculosis.

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