COPA protein linked to type I interferon induction
In a new publication in the Journal of Experimental Medicine, Professor Yanick Crow’s group investigated the link between COPA protein and type I interferon induction. August 20
Type I interferon (IFN) acts as a key component in the body’s defence against pathogens, particularly viruses, with IFN production triggered via detection of pathogen-derived nucleic acid by innate sensors. Upon detection of such nucleic acid in the cytoplasm of a cell, a cascade of signalling molecules is activated, including the protein STING (stimulator of IFN genes) found in the endoplasmic reticulum (ER). Recent observations have highlighted the trafficking of STING between the ER and the Golgi as important in the transmission, and subsequent termination, of IFN signalling. However, the precise mechanisms involved are not currently clear.
COPA syndrome is a devastating inflammatory condition affecting the lungs, kidneys and joints and is caused by heterozygous missense mutations in the COPA gene. This gene encodes the coatomer protein subunit alpha (COPA), part of the coatomer protein complex (COPI), which plays a role in the retrograde transport of proteins from the Golgi to the ER. Recent evidence indicated that COPA syndrome involves an autoinflammatory state related to type I IFN. Thus, given the importance of STING in IFN signalling, and the role COPA in the ER-Golgi axis, the Crow group hypothesised that COPA may be involved in regulating STING through intracellular transport.
In the publication led by Professor Yanick Crow, and including work of Joe Marsh from the MRC Human Genetics Unit, the research team observed upregulation of the type I IFN pathway in COPA patients carrying heterozygous mutations in the COPA gene, further supporting the description of COPA syndrome as a novel type I interferonopathy. The team then went on to establish the link between IFN signalling and COPA to be STING-dependent. Overall, the data suggest that COPA has a role in the transportation ('recycling') of STING from the Golgi to the ER, and that this represents an essential homeostatic mechanism for limiting STING-dependent IFN signalling. Importantly, in the context of COPA syndrome, this effect likely relates to the control of the IFN response to self-derived, rather than viral, DNA.
Our new work highlights important cellular mechanisms relevant to type I interferon induction by both self and non-self derived DNA, and the understanding of these pathways raises the potential of therapeutic strategies targeting the ER –Gogi axis. Indeed, these insights have already led to efforts to treat patients with COPA syndrome with ‘anti-interferon’ therapy
Publication in Journal of Experimental Medicine https://doi.org/10.1084/jem.20200600