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IGSF3 mutation identified in patient with severe COPD alters cell function and motility
Kelly S. Schweitzer, … , Constance A. Griffin, Irina Petrache
Kelly S. Schweitzer, … , Constance A. Griffin, Irina Petrache
Published June 23, 2020
Citation Information: JCI Insight. 2020;5(14):e138101. https://doi.org/10.1172/jci.insight.138101.
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Research Article Cell biology Pulmonology

IGSF3 mutation identified in patient with severe COPD alters cell function and motility

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Abstract

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.

Authors

Kelly S. Schweitzer, Natini Jinawath, Raluca Yonescu, Kevin Ni, Natalia Rush, Varodom Charoensawan, Irina Bronova, Evgeny Berdyshev, Sonia M. Leach, Lucas A. Gillenwater, Russel P. Bowler, David B. Pearse, Constance A. Griffin, Irina Petrache

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Figure 3

IGSF3 cellular localization.

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IGSF3 cellular localization.
(A and B) Presence of IGSF3 and indicated p...
(A and B) Presence of IGSF3 and indicated proteins detected by immunoblots of density gradient fractions from lymphoblastoids (A) and bronchial epithelial cells (B). (C) IGSF3 and ITGB1 detected by Western blotting in lung epithelial cells after immunoprecipitation of density gradient fractions 9 and 12 with anti-CD9 or IgG control antibodies. (D) Presence of IGSF3 or indicated proteins in either streptavidin-bound or in flow through fractions of lung epithelial cells that were cell surface biotinylated with or without CS exposure. (E) Identification of IGSF3 protein and indicated protein markers of cellular organelles in density gradient fractions of lung endothelial cells. EEA1, early endosome antigen 1; PDI, protein disulfide-isomerase; LC3B, microtubule-associated protein 1 light chain 3 β; GM130, Golgi matrix protein 130 KDa; SDHA, succinate dehydrogenase complex flavoprotein subunit A; CytC, cytochrome c.

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