TY - JOUR
T1 - IGSF3 mutation identified in patient with severe COPD alters cell function and motility
AU - Schweitzer, Kelly S.
AU - Jinawath, Natini
AU - Yonescu, Raluca
AU - Ni, Kevin
AU - Rush, Natalia
AU - Charoensawan, Varodom
AU - Bronova, Irina
AU - Berdyshev, Evgeny
AU - Leach, Sonia M.
AU - Gillenwater, Lucas A.
AU - Bowler, Russel P.
AU - Pearse, David B.
AU - Griffin, Constance A.
AU - Petrache, Irina
N1 - Funding Information:
This work was supported in part by grants sponsored by the Department of Medicine Research Micro-grant, National Jewish Health (MEDRESEARCH to KS); Wollowick Chair of Pulmonary Research, National Jewish Health (IP); Calvin H. English Chair of Medical Research and Floyd and Reba Smith Chair, Indiana University (IP); award no. RHL077328 (IP); and The Crown Property Bureau Foundation Funds (NJ and VC). The SNP study using the COPDGene cohort described was supported by award nos. U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the NIH. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer Siemens, and Sunovion. We thank Matthew Justice for assistance with ultracentrifugation and OptiPrep discontinuous gradients. We thank the COPDGene Biomarker Core faculty Katerina Kechris and Farnoush Banaei-Kashani for their assistance. We also thank Kathleen Murphy for her help with characterization of the patient translocation.
Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI.INSIGHT.138101
DO - 10.1172/JCI.INSIGHT.138101
M3 - Article
C2 - 32573489
AN - SCOPUS:85088491002
VL - 5
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 14
M1 - e138101
ER -