Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia, 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia, 750021, China.
Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia, 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia, 750021, China; Key Laboratory of Hui Ethnic Medicine Modernization Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
Microb Pathog. 2022 Jun;167:105564. doi: 10.1016/j.micpath.2022.105564. Epub 2022 May 7.
Ror2 is a primary binding partner for the non-classical Wnt signaling pathway regulator Wnt5a that plays a central role in regulating the metabolic processing of lipids within the cell. Mycobacterium tuberculosis is an intracellular pathogen that utilizes the lipid substrate cholesterol as its primary source of carbon. Cholesterol accumulation can regulate autophagy, which is in turn associated with a variety of pathological conditions. This study was designed to explore the pathways that modulate Ror2-regulated cholesterol accumulation within macrophages infected by the mycobacterium Bacillus Calmette-Guerin (BCG). BCG infection of RAW264.7 cells resulted in increased Ror2 expression, cholesterol accumulation, and autophagic activity in addition to promoting the upregulation of cholesterol synthesis-related proteins and the downregulation of cholesterol transporter proteins. Ror2 knockdown, in contrast, reversed these phenotypic changes. Treatment with T0901317 decreased the aggregation of cholesterol within cells and suppressed BCG-induced autophagy, while OX-LDL had the opposite effect. Knocking down Ror2 further reduced cholesterol levels in the context of T0901317 or OX-LDL pretreatment, alleviating BCG-induced autophagy irrespective of either of these pretreatments. Together, these data indicate that Ror2 can shape the autophagic activity induced within macrophages upon BCG infection by modulating intracellular cholesterol levels.
Ror2 是非经典 Wnt 信号通路调节剂 Wnt5a 的主要结合伴侣，在调节细胞内脂质的代谢处理中发挥核心作用。结核分枝杆菌是一种细胞内病原体，它利用脂质底物胆固醇作为其主要碳源。胆固醇积累可以调节自噬，而自噬又与多种病理状况有关。本研究旨在探索调节分枝杆菌卡介苗（BCG）感染巨噬细胞中 Ror2 调节的胆固醇积累的途径。BCG 感染 RAW264.7 细胞除了促进胆固醇合成相关蛋白的上调和胆固醇转运蛋白的下调外，还导致 Ror2 表达、胆固醇积累和自噬活性增加。相反，Ror2 的敲低逆转了这些表型变化。用 T0901317 处理可减少细胞内胆固醇的聚集并抑制 BCG 诱导的自噬，而 OX-LDL 则有相反的作用。在 T0901317 或 OX-LDL 预处理的情况下，进一步敲低 Ror2 可降低胆固醇水平，减轻 BCG 诱导的自噬，而不管这两种预处理中的哪一种。总之，这些数据表明，Ror2 可以通过调节细胞内胆固醇水平来塑造 BCG 感染巨噬细胞中诱导的自噬活性。
