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J Exp Med. 2018 Sep 3;215(9):2289-2310. doi: 10.1084/jem.20170308. Epub 2018 Aug 1.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
2
Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, The Rockefeller University, New York, NY.
3
Department of Microbiology-Immunology, Northwestern University, Chicago, IL.
4
Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Necker Hospital for Sick Children, Paris, France.
5
University Paris Descartes, Imagine Institute, Paris, France.
6
Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland.
7
Primary Immunodeficiencies Group, School of Medicine, University of Antioquia, Medellin, Colombia.
8
School of Microbiology, University of Antioquia, Medellin, Colombia.
9
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
10
Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
11
Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
12
Human Evolutionary Genetics, Pasteur Institute, Paris, France.
13
National Center for Scientific Research, URA 3012, Paris, France.
14
Center of Bioinformatics, Biostatistics and Integrative Biology, Pasteur Institute, Paris, France.
15
Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY.
16
Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
17
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
18
Fundación Universitaria de Ciencias de la Salud, Bogota, Colombia.
19
Dermatology/Oncology - Skin Cancer Unit, National Cancer Institute, Bogota, Colombia.
20
Department of Dermatology, Sylvanus Olympio Hospital, University of Lomé, Togo.
21
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.
22
Kawsar Human Genetics Research Center, Tehran, Iran.
23
Dermatology, University Hospital Basel, Basel, Switzerland.
24
Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA.
25
Department of Virology, Pasteur Institute, Paris, France.
26
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY casanova@rockefeller.edu.
27
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
28
Howard Hughes Medical Institute, New York, NY.

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 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 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.

PMID:
30068544
PMCID:
PMC6122964
[Available on 2019-03-03]
DOI:
10.1084/jem.20170308

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