COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis

Anthony Shum, Jordan Orange, James Lupski and colleagues show that mutations in the coatamer subunit gene COPA cause an autoimmune syndrome characterized by inflammatory arthritis and interstitial lung disease. They further show that the mutations disrupt ER-Golgi transport, leading to ER stress and altered T cell function. Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity 1 . 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) 2 , 3 , 4 , 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 (T H 17) response. Patient-derived CD4 + T cells also demonstrate significant skewing toward a T H 17 phenotype that is implicated in autoimmunity 5 , 6 . Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.