{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMC8 (also known as EVER2) is an integral transmembrane protein primarily localized to the endoplasmic reticulum that plays a crucial role in keratinocyte‐intrinsic immunity. Mutations in TMC8, together with those in its partner gene TMC6 (EVER1), underlie epidermodysplasia verruciformis—a rare genodermatosis marked by abnormal susceptibility to β‐human papillomaviruses and a high risk of cutaneous carcinoma. Multiple studies have revealed that loss‐of‐function mutations in TMC8 disrupt its normal function in complex formation with EVER1 (and with the calcium‐ and integrin‐binding protein CIB1), thereby impairing cellular antiviral defense and influencing zinc homeostasis. These discoveries, based on genetic mapping and mutation analyses, linked TMC8 deficiency to the development of persistent HPV lesions and eventual skin cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in viral restriction, TMC8 modulates key intracellular signaling pathways in both keratinocytes and lymphocytes. In particular, it has been implicated in the regulation of receptor‐mediated Ca²⁺ release and cellular zinc homeostasis, processes that are essential for proper activation of NF‐κB and AP-1 signaling pathways. TMC8 also interacts with adaptor proteins such as TRADD to promote TNF-α and TRAIL–dependent apoptosis, serving as a molecular brake on inappropriate cell survival that might otherwise favor viral replication. Furthermore, evidence from studies in B cells suggests that TMC8 expression can be modulated during infection by other viruses (for example, Epstein–Barr virus), highlighting its broader role in antiviral immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variation in the TMC8 gene has also been associated with susceptibility to a broader spectrum of HPV-induced malignancies beyond classical epidermodysplasia verruciformis. Polymorphisms in the TMC6/8 genomic region have been linked to cervical cancer and head and neck squamous cell carcinoma, underscoring the clinical relevance of TMC8 in modulating host–virus interactions and tumorigenesis. Moreover, recent advances in in vitro disease modelling—with, for example, induced pluripotent stem cell lines derived from patients harboring homozygous TMC8 mutations—promise to elucidate further the molecular mechanisms by which TMC8 governs antiviral immunity and cell death."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicolas Ramoz, Luis-Alfredo Rueda, Bakar Bouadjar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1044"}], "href": "https://doi.org/10.1038/ng1044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12426567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12426567"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Anita S Patel, Margaret R Karagas, Michael Pawlita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.23377"}], "href": "https://doi.org/10.1002/ijc.23377"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18224692"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18224692"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "David F McDermott, Bryan Gammon, Peter J Snijders, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Dermatol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1525-1470.2008.00853.x"}], "href": "https://doi.org/10.1111/j.1525-1470.2008.00853.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19706093"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19706093"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Maciej Lazarczyk, Cécile Dalard, Myriam Hayder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0039995"}], "href": "https://doi.org/10.1371/journal.pone.0039995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22761942"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22761942"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Eun-Kyung M Kwon, Christian R Halvorson, Peter Rady, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Merkel cell polyomavirus detection in a patient with familial epidermodysplasia verruciformis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Dermatol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/pde.12130"}], "href": "https://doi.org/10.1111/pde.12130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23535066"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23535066"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "E Imahorn, Z Yüksel, I Spoerri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Eur Acad Dermatol Venereol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jdv.14431"}], "href": "https://doi.org/10.1111/jdv.14431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28646613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28646613"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sarah Jill de Jong, Amandine Créquer, Irina Matos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20170308"}], "href": "https://doi.org/10.1084/jem.20170308"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30068544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30068544"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chuan-Jin Wu, Xing Li, Connie L Sommers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA120.013045"}], "href": "https://doi.org/10.1074/jbc.RA120.013045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32917726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32917726"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Amandine Crequer, Capucine Picard, Vincent Pedergnana, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EVER2 deficiency is associated with mild T-cell abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10875-012-9749-1"}], "href": "https://doi.org/10.1007/s10875-012-9749-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22903682"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22903682"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "G Gaud, D Guillemot, Y Jacob, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EVER2 protein binds TRADD to promote TNF-α-induced apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2013.27"}], "href": "https://doi.org/10.1038/cddis.2013.27"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23429285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23429285"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Françoise Vuillier, Guillaume Gaud, Delphine Guillemot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of the HPV-infection resistance EVER2 protein impairs NF-κB signaling pathways in keratinocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0089479"}], "href": "https://doi.org/10.1371/journal.pone.0089479"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24586810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24586810"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lalida Sirianant, Jiraporn Ousingsawat, Yuemin Tian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMC8 (EVER2) attenuates intracellular signaling by Zn2+ and Ca2+ and suppresses activation of Cl- currents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2014.09.001"}], "href": "https://doi.org/10.1016/j.cellsig.2014.09.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25220380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25220380"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Cecilia Frecha, Sébastien A Chevalier, Patrick van Uden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of the epidermodysplasia verruciformis-associated genes EVER1 and EVER2 is activated by exogenous DNA and inhibited by LMP1 oncoprotein from Epstein-Barr virus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.02936-14"}], "href": "https://doi.org/10.1128/JVI.02936-14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25378492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25378492"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "A Kalinska-Bienias, G Kostrzewa, M Malejczyk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Possible association between actinic keratosis and the rs7208422 (c.917A→T, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Dermatol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ced.12506"}], "href": "https://doi.org/10.1111/ced.12506"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25495765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25495765"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Caihua Liang, Karl T Kelsey, Michael D McClean, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A coding variant in TMC8 (EVER2) is associated with high risk HPV infection and head and neck cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0123716"}], "href": "https://doi.org/10.1371/journal.pone.0123716"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25853559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25853559"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Bettina Burger, Iris Spörri, Danielle A Stegmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Risk of Cutaneous Squamous Cell Carcinoma Development in Renal Transplant Recipients Is Independent of TMC/EVER Alterations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dermatology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000435910"}], "href": "https://doi.org/10.1159/000435910"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26227733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26227733"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Evangelia Pavlidou, Alexandros Daponte, Raquel Egea, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic polymorphisms of FAS and EVER genes in a Greek population and their susceptibility to cervical cancer: a case control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12885-016-2960-3"}], "href": "https://doi.org/10.1186/s12885-016-2960-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27899077"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27899077"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Andreas W Arnold, Bettina Burger, Erwin Kump, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homozygosity for the c.917A→T (p.N306l) polymorphism in the EVER2/TMC8 gene of two sisters with epidermodysplasia verruciformis Lewandowsky-Lutz originally described by Wilhelm Lutz."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dermatology (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000322536"}], "href": "https://doi.org/10.1159/000322536"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21196704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21196704"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Felipe A Castro, Emma L Ivansson, Markus Schmitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.26016"}], "href": "https://doi.org/10.1002/ijc.26016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21387292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21387292"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Catherine O'Blenes, Sylvia Pasternak, Andrew Issekutz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epidermodysplasia verruciformis in lipoid proteinosis: case report and discussion of pathophysiology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Dermatol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/pde.12124"}], "href": "https://doi.org/10.1111/pde.12124"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23534907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23534907"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Annika Antonsson, Matthew H Law, Rachel E Neale, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variants of EVER1 and EVER2 (TMC6 and TMC8) and human papillomavirus status in patients with mucosal squamous cell carcinoma of the head and neck."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Causes Control (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10552-016-0749-y"}], "href": "https://doi.org/10.1007/s10552-016-0749-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27097911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27097911"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Hiroki Ura, Sumihito Togi, Hisayo Hatanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Establishment of a human induced pluripotent stem cell line, KMUGMCi005-A, from a patient with Epidermodysplasia verruciformis (EV) bearing homozygous splicing donor site mutation in the TMC8 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.scr.2022.102926"}], "href": "https://doi.org/10.1016/j.scr.2022.102926"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36170758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36170758"}]}]}]}