IGSF3 mutation identified in patient with severe COPD alters cell function and motility.
IGSF3 mutation identified in patient with severe COPD alters cell function and motility.
复制标题
在严重慢性阻塞性肺病患者中发现的 IGSF3 突变会改变细胞功能和运动。
DOI：
10.1172/jci.insight.138101
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Petrache,Irina
中科院分区：
文献类型：
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作者：
Schweitzer,KellyS;Jinawath,Natini;Yonescu,Raluca;Ni,Kevin;Rush,Natalia;Charoensawan,Varodom;Bronova,Irina;Berdyshev,Evgeny;Leach,SoniaM;Gillenwater,LucasA;Bowler,RusselP;Pearse,DavidB;Griffin,ConstanceA;Petrache,Irina
吸烟(CS)和遗传易感性决定了慢性阻塞性肺疾病(COPD)的发展、进展和严重程度的风险。我们假设，偶然的平衡的染色体易位与患者患严重COPD的风险有关。我们发现46，XX，t(1；4)(p13.1；q34.3)引起免疫球蛋白超家族成员3(IGSF3)基因的断裂点，表达显著降低。COPD基因队列检查发现14个IGSF3 SNPs，其中rs1414272和rs12066192与COPD严重程度(包括COPD加重)直接相关，rs6703791与COPD严重程度负相关。我们证实IGSF3是一种与四环素相互作用的蛋白，与CD9和整合素B1共定位于四环素富集区。IGSF3缺陷患者来源的淋巴母细胞表现出基因表达的多种变化，特别是在未折叠的蛋白反应和神经酰胺通路中。IGSF3缺陷型淋巴母细胞具有较高的神经酰胺和神经鞘氨醇-1磷酸水平，较低的神经鞘糖脂和神经节苷脂水平，较少的凋亡和更多的黏附，多个TNFRSF分子发生明显变化。同样，IGSF3基因敲除增加了肺结构细胞中的神经酰胺，使它们更具粘附性，伤口修复受损，屏障功能减弱。这些发现表明，通过维持鞘磷脂和膜受体的动态平衡，IGSF3是细胞运动介导的肺损伤修复所必需的。IGSF3缺乏可增加慢性阻塞性肺疾病患者对CS所致肺损伤的易感性。
Cigarette smoking (CS) and genetic susceptibility determine the risk for development, progression, and severity of chronic obstructive pulmonary diseases (COPD). We posited that an incidental balanced reciprocal chromosomal translocation was linked to a patient’s risk of severe COPD. We determined that 46,XX,t(1;4)(p13.1;q34.3) caused a breakpoint in the immunoglobulin superfamily member 3 (IGSF3) gene, with markedly decreased expression. Examination of COPDGene cohort identified 14 IGSF3 SNPs, of which rs1414272 and rs12066192 were directly and rs6703791 inversely associated with COPD severity, including COPD exacerbations. We confirmed that IGSF3 is a tetraspanin-interacting protein that colocalized with CD9 and integrin B1 in tetraspanin-enriched domains. IGSF3-deficient patient–derived lymphoblastoids exhibited multiple alterations in gene expression, especially in the unfolded protein response and ceramide pathways. IGSF3-deficient lymphoblastoids had high ceramide and sphingosine-1 phosphate but low glycosphingolipids and ganglioside levels, and they were less apoptotic and more adherent, with marked changes in multiple TNFRSF molecules. Similarly, IGSF3 knockdown increased ceramide in lung structural cells, rendering them more adherent, with impaired wound repair and weakened barrier function. These findings suggest that, by maintaining sphingolipid and membrane receptor homeostasis, IGSF3 is required for cell mobility–mediated lung injury repair. IGSF3 deficiency may increase susceptibility to CS-induced lung injury in COPD.