Joshi Ilin V, Chan Eunice C, Lack Justin B, Liu Chengyu, Druey Kirk M
Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
NIAID Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Biol Chem. 2024 Apr;300(4):107127. doi: 10.1016/j.jbc.2024.107127. Epub 2024 Mar 2.
Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.
G蛋白信号调节蛋白（RGS）主要（但不仅限于）通过其GTP酶激活蛋白活性来限制全身G蛋白偶联受体（GPCR）介导的反应及其他反应。哮喘是一种高度常见的疾病，其特征为气道对环境刺激的高反应性（AHR），部分原因是GPCR介导的气道平滑肌收缩增强。小鼠中Rgs2或Rgs5基因缺失会增强AHR和气道平滑肌收缩，而RGS4基因敲除小鼠由于肺上皮细胞产生的支气管扩张剂前列腺素E2（PGE2）增加，AHR意外降低。在此，我们发现，与RGS4基因敲除小鼠或野生型对照相比，携带编码点突变（N128A）的Rgs4等位基因的敲入小鼠，其RGS4 GTP酶激活蛋白活性大幅降低，AHR增加，气道PGE2水平降低，且GPCR诱导的支气管收缩增强。RGS4与PI3K的p85α亚基相互作用，并抑制气道上皮细胞中转化生长因子β引发的PI3K依赖性PGE2分泌。这些发现共同表明，RGS4部分通过以G蛋白非依赖方式调节气道炎症环境来影响哮喘严重程度。
