Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization

Abstract

CCHCR1 (Coiled-Coil α-Helical Rod protein 1), within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5′-region of the gene contains a SNP (rs3130453) that controls a 5′-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10−7). Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.

Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders

“…One of the disrupted interactions is the interaction between TPM3 and troponin, which was shown to be vital for the transduction of calcium-induced signals required for muscle contraction (Gunning et al, 1990). Two other perturbed interactors, HSF2, involved in myotube regeneration (McArdle et al, 2006), and CCHCR1, required for cytoskeleton organization (Tervaniemi et al, 2012), could also be of disease relevance. In contrast to these edgetic mutations, the quasi-WT mutation M9R causes a different disease, nemaline myopathy.…”

Genetic architecture of gene expression underlying variation in host response to porcine reproductive and respiratory syndrome virus infection

“…Among our candidate genes for WG, CMPK2 has been reported to be associated with monocytic/macrophage terminal differentiation27 and CCHCR1 might function in EGFR-STAT3 signaling and innate immunity28. The gene CCHCR1 was significantly down-regulated at 4 DPI compared to day 0 and was expressed at a lower level at all DPI in individuals homozygous for the susceptibility allele.…”

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

“…In psoriatic lesions, CCHCR1 expression is more abundant and is enhanced in basal keratinocytes and in dermal papillae (Tiala et al 2008). CCHCR1 interact with StAR for steroid synthesis in the mitochondria (Tervaniemi et al 2012) and in lesional psoriatic skin, they show an inverse expression pattern. Furthermore, a correlation between CCHCR1 and VDR expression is demonstrated by the downregulation of VDR and overexpression of CCHCR1 in the mice keratinocytes (Tiala et al 2007).…”