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The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to ?-papillomaviruses.

ABSTRACT: Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human ?-papillomaviruses (?-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by ?-HPV16 and ?-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to ?-HPVs of EV patients.

SUBMITTER: de Jong SJ

PROVIDER: S-EPMC6122964 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses.

de Jong Sarah Jill SJ Créquer Amandine A Matos Irina I Hum David D Gunasekharan Vignesh V Lorenzo Lazaro L Jabot-Hanin Fabienne F Imahorn Elias E Arias Andres A AA Vahidnezhad Hassan H Youssefian Leila L Markle Janet G JG Patin Etienne E D'Amico Aurelia A Wang Claire Q F CQF Full Florian F Ensser Armin A Leisner Tina M TM Parise Leslie V LV Bouaziz Matthieu M Maya Nataly Portilla NP Cadena Xavier Rueda XR Saka Bayaki B Saeidian Amir Hossein AH Aghazadeh Nessa N Zeinali Sirous S Itin Peter P Krueger James G JG Laimins Lou L Abel Laurent L Fuchs Elaine E Uitto Jouni J Franco Jose Luis JL Burger Bettina B Orth Gérard G Jouanguy Emmanuelle E Casanova Jean-Laurent JL

The Journal of experimental medicine 20180801 9

Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those ...[more]

PMID: 30068544

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Project description:Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5? was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5? is almost powerless to restrict HIV-1. However, human TRIM5? potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5? represents the restriction factor previously designated as Ref1. African green monkey TRIM5? represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5? is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5?. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between ?-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5? and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5? is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5?. Recently, human TRIM5? was shown to activate signaling pathways that lead to activation of NF-?B and AP-1 by interacting with TAK1 complex. TRIM5? is thus involved in control of viral infection in multiple ways.

Dataset Information

The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to ?-papillomaviruses.

Publications

The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses.

Similar Datasets

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