Dai Ting, Zhao Ziyue, Zhu Tingfang, Fei Chenjie, Nie Li, Chen Jiong
State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.
Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, China.
Front Immunol. 2024 May 29;15:1401626. doi: 10.3389/fimmu.2024.1401626. eCollection 2024.
Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 zDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all zDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, zDHHC23 exhibited the most pronounced upregulation following () infection of macrophage/monocyte cells (MO/MΦ). Silencing zDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, zDHHC23 facilitated M2-type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon zDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by infection. These findings highlight the non-PAT immunomodulatory function of zDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting zDHHC23 as a potential therapeutic target for immune modulation in aquatic species.
含锌指天冬氨酸-组氨酸-组氨酸-半胱氨酸基序（zDHHC）的蛋白质，以其棕榈酰转移酶（PAT）活性而闻名，在包括免疫调节在内的多种细胞过程中发挥关键作用。然而，它们的非棕榈酰转移酶免疫调节功能以及在硬骨鱼免疫反应中的作用仍未得到充分研究。在本研究中，我们系统地鉴定了大黄鱼中的zDHHC家族，共识别出22个成员。系统发育分析表明，这22个zDHHC中的每一个都与其他硬骨鱼物种的直系同源物形成了不同的聚类。此外，通过三级结构预测证实，所有zDHHC都具有高度保守的DHHC结构域。值得注意的是，在巨噬细胞/单核细胞（MO/MΦ）感染迟缓爱德华氏菌后，zDHHC23的上调最为明显。在感染期间，沉默zDHHC23会导致MO/MΦ中促炎细胞因子表达增加，抗炎细胞因子水平降低，表明其具有抗炎作用。在功能上，zDHHC23促进了M2型巨噬细胞极化，这一点可通过zDHHC23敲低后MO/MΦ向促炎M1表型的显著转变以及对迟缓爱德华氏菌感染诱导的MO/MΦ坏死性凋亡的抑制来证明。这些发现突出了zDHHC23在硬骨鱼免疫调节中的非PAT免疫调节功能，拓宽了我们对zDHHC蛋白在宿主-病原体相互作用中的理解，表明zDHHC23作为水生物种免疫调节的潜在治疗靶点。
