Centrosomal Localization of the Psoriasis Candidate Gene Product , CCHCR 1 , Supports a Role in Cytoskeletal Organization Tervaniemi

CCHCR1 (Coiled-Coil a-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 59-region of the gene contains a SNP (rs3130453) that controls a 59-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). 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 isoformand 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. Citation: Tervaniemi MH, Siitonen HA, Söderhäll C, Minhas G, Vuola J, et al. (2012) Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization. PLoS ONE 7(11): e49920. doi:10.1371/journal.pone.0049920 Editor: Giuseppe Novelli, Tor Vergata University of Rome, Italy Received August 6, 2012; Accepted October 15, 2012; Published November 26, 2012 Copyright: 2012 Tervaniemi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by Academy of Finland (grant no. 130360; no. 1255560), Finska Läkaresällskapet, Helsinki University Research Funds, Sigrid Jusélius Foundation, Helsinki University Hospital Research Funds (TYH2009233), Swedish Research Council and Swedish Governmental Agency for Innovation Systems Vinnova. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: juha.kere@ki.se