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

Abstract

Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER1) or (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 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 α-HPV16 and γ-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 β-HPVs of EV patients.

Inherited human IFN-γ deficiency underlies mycobacterial disease

“…PLINK software (http://zzz.bwh.harvard.edu/plink/) was used to further filter SNPs with population-based filters according to the ethnicity of the kindred. A subset of 163,807 autosomal SNP markers common to the 2 genotyping arrays and optimized to decrease their linkage disequilibrium (LD) was used for linkage analysis, as previously described (88). Parametric multipoint linkage analyses were performed with MERLIN (http://csg.sph.umich.…”

Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance

“…EVER1 and EVER2 are able to repress zinc-dependent transcription. However, in a different study, endogenous deficiencies of neither protein were found to be associated with overt disturbed zinc homeostasis [57].…”

Verrucous pilar cysts infected with beta human papillomavirus

“…HPV‐24 is among the HPV species associated with epidermodysplasia verruciformis (EV), a genetic or acquired skin disease characterized by multiple pre‐malignant verrucous papules and macules caused by chronic HPV infection . Genetic EV typically results from loss of function mutations in EVER1, EVER2, or CIB1, while acquired EV may result from iatrogenic immunosuppression in organ transplant patients, HIV infection, or other medical conditions leading to compromised immune function. In fact, ruptured epidermoid cysts infected with HPV‐24, as well as EV‐associated HPV‐20 and HPV‐80, have been reported in one patient with idiopathic CD4 lymphopenia and chronic Mycobacterium avium intracellulare infection .…”

“…HPV-24 is among the HPV species associated with epidermodysplasia verruciformis (EV), a genetic or acquired skin disease characterized by multiple premalignant verrucous papules and macules caused by chronic HPV infection. 19 Genetic EV typically results from loss of function mutations in EVER1, EVER2, or CIB1, 20,21 Mycobacterium avium intracellulare infection. 22 In contrast, β HPV species typically produce asymptomatic infection in immunocompetent reported for bacteria and fungi.…”