"Sfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P₂ Pathway"

作者全名："Zhang, Huan; Meng, Ling; Liu, Yang; Jiang, Jinlong; He, Zhenting; Qin, Jingjing; Wang, Cuihong; Yang, Meiting; He, Ke; Yang, Jie; Chen, Ketong; He, Qinke; Tang, Wenwen; Fan, Sijia; Ren, Chunguang"

作者地址："[Zhang, Huan; Meng, Ling; Liu, Yang; Jiang, Jinlong; He, Zhenting; Qin, Jingjing; Wang, Cuihong; Yang, Meiting; He, Ke; Yang, Jie; Chen, Ketong; He, Qinke; Fan, Sijia; Ren, Chunguang] Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing, Peoples R China; [Tang, Wenwen] Yale Univ, Sch Med, Dept Pharmacol, Vasc Biol & Therapeut Program, New Haven, CT 06510 USA"

通信作者："Fan, SJ; Ren, CG (通讯作者)，Chongqing Med Univ, Sch Basis Med Sci, Dept Cell Biol, Chongqing, Peoples R China."

来源：JOURNAL OF IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001160372900016

JCR分区：Q2

影响因子：3.6

年份：2023

卷号：211

期号：3

开始页：462

结束页：473

文献类型：Article

关键词：　

摘要："Cell spreading is an initial and critical step in neutrophil adhesion and migration, leading to neutrophil recruitment to inflammatory tissues. Sideroflexin (Sfxn) family proteins are metabolite transporters located in the mitochondrial membrane. Recombinant SFXN5 protein is a citrate transporter in vitro; however, whether Sfxn5 regulates any cellular behavior or function remains unknown. In this study, we found that small interfering RNA transfection or morpholino injection achieving Sfxn5 deficiency in neutrophils significantly decreased neutrophil recruitment in mice and zebrafish, respectively. Sfxn5 deficiency impaired neutrophil spreading and spreading-associated cellular phenotypes, such as cell adhesion, chemotaxis, and ROS production. Actin polymerization is critical for neutrophil spreading, and we found that actin polymerization in spreading neutrophils was partially inhibited by Sfxn5 deficiency. Mechanistically, we observed that the levels of cytosolic citrate and its downstream metabolic products, acetyl-CoA and cholesterol, were decreased in Sfxn5-deficient neutrophils. The levels of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2), a mediator for the regulation of actin polymerization by cholesterol, were reduced in the plasma membrane of Sfxn5-deficient neutrophils. Exogenous supplementation with citrate or cholesterol partially reversed the reduction in PI(4,5)P-2 levels, defective neutrophil actin polymerization, and cell spreading. Altogether, we demonstrated that Sfxn5 maintains cytosolic citrate levels and ensures the synthesis of sufficient cholesterol to promote actin polymerization in a PI(4,5)P-2-dependent manner during neutrophil spreading, which is essential for the eventual inflammatory recruitment of neutrophils. Our study revealed the importance of Sfxn5 in neutrophil spreading and migration, thus identifying, to our knowledge, for the first time, the physiological cellular functions of the Sfxn5 gene."

基金机构："National Natural Science Foundation of China [32170766]; China Postdoctoral Science Foundation [281696]; Chongqing Science and Technology Bureau [CSTB2022BSXM-JCX0036, CSTB2022NSCQ-MSX1682, cstc2021jcyj-bshX0080]; Chongqing Human Resources and Social Security Bureau [cx2020029]; Chongqing Medical University Talent Development Program Grant [BJRC202101]; Chongqing Medical University Program for Youth Innovation in Future Medicine Grant [W0052]; Chongqing Medical University Scientific Research and Innovation Experiment Project [202206]"

基金资助正文："This work was supported by the National Natural Science Foundation of China Grant 32170766, China Postdoctoral Science Foundation Grant 281696, Chongqing Science and Technology Bureau Grants CSTB2022BSXM-JCX0036, CSTB2022NSCQ-MSX1682, and cstc2021jcyj-bshX0080, Chongqing Human Resources and Social Security Bureau Grant cx2020029, Chongqing Medical University Talent Development Program Grant BJRC202101, Chongqing Medical University Program for Youth Innovation in Future Medicine Grant W0052, and by Chongqing Medical University Scientific Research and Innovation Experiment Project Grant 202206."