학술논문
COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis
Document Type
article
Author
Watkin, Levi B; Jessen, Birthe; Wiszniewski, Wojciech; Vece, Timothy J; Jan, Max; Sha, Youbao; Thamsen, Maike; Santos-Cortez, Regie LP; Lee, Kwanghyuk; Gambin, Tomasz; Forbes, Lisa R; Law, Christopher S; Stray-Pedersen, Asbjørg; Cheng, Mickie H; Mace, Emily M; Anderson, Mark S; Liu, Dongfang; Tang, Ling Fung; Nicholas, Sarah K; Nahmod, Karen; Makedonas, George; Canter, Debra L; Kwok, Pui-Yan; Hicks, John; Jones, Kirk D; Penney, Samantha; Jhangiani, Shalini N; Rosenblum, Michael D; Dell, Sharon D; Waterfield, Michael R; Papa, Feroz R; Muzny, Donna M; Zaitlen, Noah; Leal, Suzanne M; Gonzaga-Jauregui, Claudia; Boerwinkle, Eric; Eissa, N Tony; Gibbs, Richard A; Lupski, James R; Orange, Jordan S; Shum, Anthony K
Source
Nature Genetics. 47(6)
Subject
Language
Abstract
Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.