EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis

• DOI: 10.1038/s41419-022-05370-y
• Publication Date: 2022-11-07T19:06:01Z
• Authors: Xuedi Zhang; Cuiping Chen; Chunxiu Ling; Shuhua Luo; Ziying Xiong; Xiaolei Liu; Chaoxiong Liao; Pengyun Xie; Youtan Liu; Liangqing Zhang; Zhanghui Chen; Zhifeng Liu; Jing Tang
• Keywords: Rab

Abstract EGFR phosphorylation is required for TLR4-mediated macrophage activation during sepsis. However, whether and how intracellular transported endotoxemia have largely been unknown. Here, we show that LPS promotes high levels cell surface expression of in macrophages through two different transport mechanisms. On one hand, Rab10 EEA1-mediated the membrane translocation from Golgi. other prevents its endocytosis a kinase activity-dependent manner. Erlotinib, an tyrosine inhibitor, significantly reduced LPS-activated macrophage. Mechanistically, upon induced TLR4/EGFR phosphorylation, MAPK14 phosphorylated Rab7a at S72 impaired receptor late endocytosis, which maintains localization though blocking lysosomal degradation. Meanwhile, Rab5a also involved early EGFR. Subsequently, inhibition switches M1 phenotype to M2 alleviates sepsis-induced acute lung injury. Mechanistic study demonstrated Erlotinib suppressed glycolysis-dependent polarization via PKM2/HIF-1ɑ pathway promoted up-regulating PPARγ glutamine metabolism. Collectively, our data elucidated more in-depth mechanism activation, provided stronger evidence supporting as potential therapeutic target treatment