Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization Mari H. Tervaniemi 1,2,3 , H. Annika Siitonen 1,2,3 , Cilla So ¨ derha ¨ll 4 , Gurinder Minhas 1,2,3 , Jyrki Vuola 5 , Inkeri Tiala 1,2,3 , Raija Sormunen 6 , Lena Samuelsson 7 , Sari Suomela 8 , Juha Kere 1,2,3,4,9 *, Outi Elomaa 1,2,3 1 Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 2 Research Program’s Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland, 3 Folkha ¨lsan Institute of Genetics, Helsinki, Finland, 4 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden, 5 Helsinki Burn Centre, Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland, 6 Biocenter Oulu, Department of Pathology, University of Oulu, Oulu, Finland, 7 Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden, 8 Department of Dermatology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland, 9 Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden Abstract 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 27 ). 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. Citation: Tervaniemi MH, Siitonen HA, So ¨ derha ¨ll 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: ß 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 La ¨karesa ¨llskapet, Helsinki University Research Funds, Sigrid Juse ´lius 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 Introduction Psoriasis is a chronic skin disease that affects 2–3% of people with European descent and is less common in other populations such as in Asia and Africa [1]. The most important chromosomal region for psoriasis predisposition is PSORS1 in the Human Leukocyte Antigen region (HLA, 6p21.3) where also CCHCR1 (Coiled-Coil a-Helical Rod protein 1), by position a plausible psoriasis candidate gene, is located [2,3]. Even though CCHCR1 resides in the chromosomal region showing the strongest associations in genome-wide association studies [4], its role and function in the pathogenesis of psoriasis is still unclear. The CCHCR1 gene is highly polymorphic and has the allele CCHCR1*WWCC associated with psoriasis in several populations [2,3,5]. ‘‘WWCC’’ stands for the amino acids in the psoriasis risk haplotype, whereas in the non-risk haplotype the corresponding amino acids are RRGS. The CCHCR1 protein does not belong to any known protein family but is predicted to be a rod-like protein, with an alpha-helical coiled coil structure. The expression of CCHCR1 is different in psoriatic lesions when compared with healthy skin or other hyperproliferative skin disorders [6]. We and others have demonstrated that CCHCR1 regulates the synthesis of steroids from cholesterol in mitochondria by interacting with the steroidogenic activator protein StAR [7,8]. Interestingly, a recent gene expression analysis revealed evidence for decreased lipid biosynthesis in uninvolved psoriatic skin, supporting the role of altered lipid metabolism in the pathogenesis of psoriasis [9]. Our recent findings showed that overexpression of CCHCR1 affects keratinocyte proliferation in transgenic mice. The most evident effect was observable after wounding and treatment with 12-O- tetradecanoyl-13-acetate (TPA); the number of proliferating keratinocytes was decreased and wound healing delayed in mice with the CCHCR1*WWCC risk allele [10]. Furthermore, the expression of several genes relevant in psoriasis pathogenesis were altered, these including cytokeratins 6, 16, and, 17, and genes of the epidermal differentiation complex region on the PSORS4 locus PLOS ONE | www.plosone.org 1 November 2012 | Volume 7 | Issue 11 | e49920