A Pivotal Role for CXCL12 Signaling in HPV-Mediated Transformation of Keratinocytes: Clues to Understanding HPV-Pathogenesis in WHIM Syndrome

Ken Y. Chow (1) , Emilie Brotin (2) , Youcef Ben Khalifa (3) , Laëtitia Carthagéna (4) , Sébastien Teissier (5) , Anne Danckaert (6) , Jean-Luc Galzi (7) , Fernando Arenzana-Seisdedos (1) , Françoise Thierry (5) , Françoise Bachelerie (8)

1 Pathogénie Virale Moléculaire
2 BioTICLA - Biologie et Thérapies Innovantes des Cancers Localement Agressifs
3 DyLAH - Dynamique des Lyssavirus et Adaptation à l'Hôte
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 EGM - Expression Génétique et Maladies
6 CITECH - Imagopole
7 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
8 Cytokines, chimiokines et immunopathologie

The WHIM syndrome, which features high susceptibility to human papillomavirus (HPV) infection, is a rare immunodeficiency associated with autosomal dominant heterozygous mutations of the CXCR4 che-mokine receptor. CXCL12 and its receptors, CXCR4 and CXCR7, are linked to tumorigenesis, and we reported that abnormal expression of CXCL12 in epidermal keratinocytes correlates with HPV infection. However, the HPV-related pathologies observed in WHIM patients remain mechanistically unexplained. We show that keratinocytes immortalized by oncogenic HPV16 or HPV18 upregulate CXCL12 and its receptors in a manner dependent upon expression of the viral proteins E6 and E7. Autocrine signaling activated by CXCL12-engagement of its receptors controls motility and survival of the infected cells. Strikingly, expression of a WHIM syndrome-related gain-of-function CXCR4 mutant confers transforming capacity to HPV18-immortalized keratinocytes. These results establish a pivotal role for CXCL12 signaling in HPV-mediated transformation and provide a mechanistic basis for understanding HPV pathogenesis in WHIM syndrome.

Domaines: Chimie; Chimie thérapeutique; Sciences du Vivant [q-bio]; Sciences pharmaceutiques; Pharmacologie

Ken Y. Chow, Emilie Brotin, Youcef Ben Khalifa, Laëtitia Carthagéna, Sébastien Teissier, et al.. A Pivotal Role for CXCL12 Signaling in HPV-Mediated Transformation of Keratinocytes: Clues to Understanding HPV-Pathogenesis in WHIM Syndrome. Cell Host and Microbe, 2010, 8 (6), pp.523-533. ⟨10.1016/j.chom.2010.11.006⟩. ⟨hal-02194374⟩