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

Nat Genet 2015 Jun 20;47(6):654-60. Epub 2015 Apr 20.

1] Department of Medicine, University of California, San Francisco, San Francisco, California, USA. [2] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513663PMC
June 2015
55 Reads

Publication Analysis

Top Keywords

syndrome autoimmunity
8
mutant copa
8
lung disease
8
copa
5
coat protein
4
defective intracellular
4
transport coat
4
protein complex
4
intracellular transport
4
complex copi
4
proteins targeted
4
targeted retrograde
4
retrograde golgi-to-er
4
binding proteins
4
impair binding
4
copi copa
4
copa variants
4
variants impair
4
leads defective
4
hypothesizing mutant
4

Similar Publications