Hu Chun Fang, Liao Xiao Yan, Xu Dan Dan, Ruan Yi Bin, Gao Feng Guang
Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.
Technology Center, China Tobacco Guizhou Industrial Co., Ltd., Guiyang 550003, China.
Vaccines (Basel). 2021 Mar 19;9(3):278. doi: 10.3390/vaccines9030278.
K48-linked ubiquitination determining antigen degradation and the endosomal recruitments of p97 and Sec61 plays vital roles in dendritic cell (DC) cross-presentation. Our previous studies revealed that nicotine treatment increases bone marrow-derived dendritic cell (BM-DC) cross-presentation and promotes BM-DC-based cytotoxic T lymphocyte (CTL) priming. But the effect of nicotine on K48-linked ubiquitination and the mechanism of nicotine-increased BM-DC cross-presentation are still uncertain. In this study, we first demonstrated that ex vivo nicotine administration obviously increased K48-linked ubiquitination in BM-DC. Then, we found that K48-linked ubiquitination was essential for nicotine-augmented cross-presentation, BM-DC-based CTL priming, and thereby the superior cytolytic capacity of DC-activated CTL. Importantly, K48-linked ubiquitination was verified to be necessary for nicotine-augmented endosomal recruitments of p97 and Sec61. Importantly, mannose receptor (MR), which is an important antigenic receptor for cross-presentation, was exactly catalyzed with K48-linked ubiquitination by the treatment with nicotine. Thus, these data suggested that K48-linked ubiquitination contributes to the superior adaptive immunity of nicotine-administrated BM-DC. Regulating K48-linked ubiquitination might have therapeutic potential for DC-mediated immune therapy.
K48连接的泛素化决定抗原降解以及p97和Sec61在内体中的募集，在树突状细胞（DC）交叉呈递中发挥着至关重要的作用。我们之前的研究表明，尼古丁处理可增强骨髓来源的树突状细胞（BM-DC）的交叉呈递，并促进基于BM-DC的细胞毒性T淋巴细胞（CTL）启动。但是尼古丁对K48连接的泛素化的影响以及尼古丁增强BM-DC交叉呈递的机制仍不明确。在本研究中，我们首先证明，体外给予尼古丁可显著增加BM-DC中K48连接的泛素化。然后，我们发现K48连接的泛素化对于尼古丁增强的交叉呈递、基于BM-DC的CTL启动以及由此产生的DC激活的CTL的卓越溶细胞能力至关重要。重要的是，已证实K48连接的泛素化对于尼古丁增强的p97和Sec61在内体中的募集是必要的。重要的是，甘露糖受体（MR）是交叉呈递的重要抗原受体，经尼古丁处理后确实被K48连接的泛素化催化。因此，这些数据表明，K48连接的泛素化有助于尼古丁处理的BM-DC具有卓越的适应性免疫。调节K48连接的泛素化可能对DC介导的免疫治疗具有治疗潜力。
