Intracellular signalling pathways and cytoskeletal functions converge on the psoriasis candidate gene CCHCR1 expressed at P-bodies and centrosomes

Abstract

BackgroundCCHCR1 (Coiled-Coil α-Helical Rod protein 1) is a putative psoriasis candidate gene with the risk alleles CCHCR1*WWCC and *Iso3, the latter inhibiting the translation of isoform 1. CCHCR1 was recently shown to be a centrosomal protein, as well as a component of cytoplasmic processing bodies (P-bodies) that regulate mRNA turnover. The function of CCHCR1 has remained unsettled, partly because of the inconsistent findings; it has been shown to play a wide variety of roles in divergent processes, e.g., cell proliferation and steroidogenesis. Here we utilized RNA sequencing (RNAseq) using HEK293 cells overexpressing isoforms 1 or 3 (Iso1, Iso3 cells), in combination with the coding non-risk or risk (*WWCC) haplotype of CCHCR1. Our aim was to study the overall role of CCHCR1 and the effects of its variants.ResultsThe overexpression of CCHCR1 variants in HEK293 cells resulted in cell line-specific expression profiles though several similarities were observable. Overall the Iso1 and Iso3 cells showed a clear isoform-specific clustering as two separate groups, and the Non-risk and Risk cells often exhibited opposite effects. The RNAseq supported a role for CCHCR1 in the centrosomes and P-bodies; the most highlighted pathways included regulation of cytoskeleton, adherens and tight junctions, mRNA surveillance and RNA transport. Interestingly, both the RNAseq and immunofluorescent localization revealed variant-specific differences for CCHCR1 within the P-bodies.ConclusionsCCHCR1 influenced a wide variety of signaling pathways, which could reflect its active role in the P-bodies and centrosomes that both are linked to the cytoskeleton; as a centrosomal P-body protein CCHCR1 may regulate diverse cytoskeleton-mediated functions, such as cell adhesion and -division. The present findings may explain the previous inconsistent observations about the functions of CCHCR1.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4810-y) contains supplementary material, which is available to authorized users.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

“…Across our two severity phenotypes (hospitalized vs. non-hospitalized cases; severe vs. non-hospitalized cases), we found no new associations at P<5x10 -8 ( Supplementary Figure 1), indicating that these analyses were underpowered for genome-wide discovery. To increase power, we combined results from our COVID-19 hospitalization phenotype (2,175 cases vs. 651,047 controls) with those from two published GWAS [19,21], for a combined sample size of 5,461 hospitalized cases and 661,632 controls with no record of SARS-CoV-2 infection. In this larger analysis of disease risk, seven loci reached genome-wide significance (Figure 2), including the four highlighted by the replication analysis above (LZTFL1, MHC, DPP9 and IFNAR2) and three novel associations ( Table 1): rs79833209 near CCNG1 (5q34; MAF=2%, OR=1.54, P=2x10 -8 ); rs4782327 in ACSF3 (16q24.3; MAF=22%, OR=1.17, P=8x10 -9 ); and rs12461764 in FPR1 (19q13.41; MAF=35%, OR=1.18, P=10 -8 ).…”

Discovery of increased epidermal DNAH10 expression after regeneration of dermis in a randomized with-in person trial — reflections on psoriatic inflammation

“…Based on these results, we hypothesized that expression of DNAH10 would be affected in active psoriatic epidermis characterized by early dermal inflammation, keratinocyte hyperproliferation, and defective epidermal barrier function 30–32 . Moreover, for our previous work on psoriasis and keratinocytes 27,28,33 we had collected specifically thin STSG samples from both active inflamed and normal skin areas. To investigate whether DNAH10 would be differently present or distributed in normal skin, in samples of healthy controls compared to those of both lesional and non-lesional skin of psoriasis patients, the samples were immunohistochemically stained with anti-DNAH10 antibody.…”

Analysis of Glucocorticoid-Related Genes Reveal CCHCR1 as a New Candidate Gene for Type 2 Diabetes

“…The CCHCR1 gene encodes a protein with 5 coiled-coil α-helical rod protein domains. The CCHCR1 protein has been linked to multiple, distinct biological processes, such as steroidogenesis, cytoskeleton regulation, and muscle differentiation [ 52 , 55 , 56 ]. CCHCR1 promotes steroidogenesis through its interaction with the mitochondrial steroidogenic acute regulatory protein (StAR), which regulates cholesterol transport to the inner mitochondrial membrane, a rate-limiting step in steroid biosynthesis [ 57 , 58 ].…”

“…CCHCR1 promotes steroidogenesis through its interaction with the mitochondrial steroidogenic acute regulatory protein (StAR), which regulates cholesterol transport to the inner mitochondrial membrane, a rate-limiting step in steroid biosynthesis [ 57 , 58 ]. CCHCR1 localizes to either the centrosome or P-bodies affecting cytoskeleton-mediated processes, such as cell division, cell adhesion, and messenger RNA transport [ 52 , 55 , 59 ]. While the connection to steroidogenesis may suggest a physiological mechanism underlying our observed association between CCHCR1 SNVs and T2D, the cellular and physiological actions of CCHCR1 need further study to establish how genetic perturbation of CCHCR1 affects T2D risk.…”