Yuan Qianying, Ren Chunguang, Xu Wenwen, Petri Björn, Zhang Jiasheng, Zhang Yong, Kubes Paul, Wu Dianqing, Tang Wenwen
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06520, USA.
Snyder Institute for Chronic Diseases Mouse Phenomics Resource Laboratory, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Cell Rep. 2017 Jun 20;19(12):2586-2597. doi: 10.1016/j.celrep.2017.05.080.
Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to guanosine triphosphate (GTP)-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury.
极化囊泡运输在细胞极化中起重要作用，但这一过程的潜在机制及其在先天免疫反应中的作用尚不清楚。在此，我们描述了一种磷酸化调节的极化机制，该机制在炎症反应期间对中性粒细胞与内皮细胞的黏附很重要。我们发现蛋白激酶PKN1使RPH3A磷酸化，这增强了RPH3A与鸟苷三磷酸（GTP）结合的RAB21的结合。这些相互作用对于RAB21和RPH3A在中性粒细胞中的极化定位很重要，这导致PIP5K1C90极化。与PIP5K1C90极化的作用一致，缺乏PKN1或RPH3A会损害中性粒细胞整合素激活、与内皮细胞的黏附以及在炎症模型中的浸润。此外，PKN1的髓系特异性缺失可减轻肾缺血再灌注模型中的组织损伤。因此，本研究描述了中性粒细胞中蛋白质极化的机制，并确定了一个潜在的蛋白激酶靶点，用于对再灌注相关组织损伤进行治疗干预。
