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zDHHC8 suppresses infection-induced necroptosis in monocyte/macrophages through palmitoylation of necrosome components in large yellow croaker (Larimichthys crocea).

Ziyue Zhao,Tingfang Zhu,Chenjie Fei,Li Nie,Jiong Chen

Published 2025 in International Journal of Biological Macromolecules

ABSTRACT

Palmitoylation, a reversible post-translational modification, regulates a wide range of cellular processes by modulating protein localization, stability, and interactions. The zinc finger Asp-His-His-Cys (zDHHC) family of palmitoyltransferases is central to this process, yet their functions in immune cell death of lower vertebrates, remain poorly understood. Here, we investigate the role of zDHHC8 in modulating immune responses and necroptosis during infection in large yellow croaker (LczDHHC8). We demonstrate that LczDHHC8 is significantly upregulated in monocyte/macrophages (MO/MΦ) during Pseudomonas plecoglossicida infection and plays a key role in promoting pro-inflammatory cytokine production and M1 macrophage polarization. Through acyl-biotin exchange (ABE) assays and liquid chromatography-mass spectrometry (LC-MS/MS), we show that LczDHHC8 suppresses the palmitoylation of necrosome components, including receptor-interacting protein kinases 1 (RIPK1), receptor-interacting protein kinases 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL), thereby influencing necroptosis of MO/MΦ. LczDHHC8 deficiency exacerbates necroptosis, evidenced by increased phosphorylation of necroptosis-related proteins and enhanced cell death. Our findings suggest that LczDHHC8 may negatively regulates necroptosis through facilitating the palmitoylation of necrosome components, thereby influencing MO/MΦ function by modulating immune responses and cell survival during infection. This study provides novel insights into the immune regulatory roles of palmitoylation in teleosts and emphasizes the importance of LczDHHC8 in the modulation of necroptosis, which may have broader implications for understanding host-pathogen interactions and inflammatory responses in vertebrates.

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