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Chloe Stanton, Elod Kortvely, Caroline Hayward, Marius Ueffing, Alan Wright; The serine protease HTRA1 is a potential regulator of the inflammatory cytokine GDF15. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5006.
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© ARVO (1962-2015); The Authors (2016-present)
An AMD risk locus on chr10q26 spans two genes - ARMS2 and HTRA1 - and controversy exists as to whether one or both genes contribute to AMD. This study was performed to investigate the protein interaction network of the serine protease HTRA1 (high-temperature requirement A-1) and to elucidate a possible role in AMD pathogenesis.
Potential interacting partners of HTRA1 were identified in a yeast two-hybrid screen performed using a placental cDNA library. Protein interactions were subsequently verified using recombinant proteins in pull-down assays. Proteins found to interact directly with HTRA1 were subjected to protease activity assays to identify substrates of the protease. Plasma GDF15 was measured by ELISA, and gene expression determined by RT-PCR.
Growth differentiation factor 15 (GDF15), a divergent member of the TGFβ superfamily, with a proposed role in mediating inflammation, interacts directly with HTRA1 in vitro. ProGDF15 is a substrate for the HTRA1 protease in vitro. GDF15 and HTRA1 are expressed at very low levels by monocyte-like cells, and their expression is highly upregulated in activated macrophages. Plasma GDF15 is significantly elevated in AMD cases carrying the chromosome 10 risk haplotype, relative to disease-free controls, or to AMD cases not carrying the chromosome 10 risk haplotype.
ProGDF15 is a substrate for the HTRA1 protease in vitro, suggesting a regulatory role for the protease on this inflammatory cytokine. Given the previously described role of GDF15, the substantial genetic risk for AMD associated with the chromosome 10 risk haplotype, and the involvement of macrophages in AMD, GDF15 may contribute towards pathological inflammation observed in the disease. Further work to understand the genetic contribution to regulating GDF15 expression in the general population, and in disease, and to determine the biological significance of the interaction between HTRA1 and GDF15 is on-going.
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