Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway

• Published in: Medical microbiology and immunology Vol. 209; no. 4; pp. 461 - 471
• Main Authors: Mikuličić, Snježana, Fritzen, Anna, Scheffer, Konstanze, Strunk, Johannes, Cabañas, Carlos, Sperrhacke, Maria, Reiss, Karina, Florin, Luise
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2020; Springer Nature B.V
• Subjects: ADAM17 Protein - genetics; ADAM17 Protein - metabolism; Biomedical and Life Sciences; Biomedicine; CD9 antigen; Cell surface; Cervical cancer; Cervix; Endocytosis; Epithelial cells; Extracellular signal-regulated kinase; Gene Expression Regulation; Gene Knockdown Techniques; HaCaT Cells; HeLa Cells; Human papillomavirus; Human papillomavirus 16; Humans; Immunology; Infections; Keratinocytes; Keratinocytes - virology; MAP Kinase Signaling System; Medical Microbiology; Original Investigation; Papillomaviridae; Papillomavirus Infections - metabolism; Papillomavirus Infections - virology; Phosphorylation; Signal transduction; Tetraspanin 29 - genetics; Tetraspanin 29 - metabolism; Tetraspanins in infections and immunity; Transforming Growth Factor alpha - metabolism; Transforming growth factor-a; Tumors; Virology; Virus Internalization; Papillomavirus; Infection; Entry; ADAM17; Receptor; L1; TSPAN29; CD9; HPV; Tetraspanin
• ISSN: 0300-8584; 1432-1831
• DOI: 10.1007/s00430-020-00671-5

Human papillomaviruses (HPV) are causative agents of various tumours such as cervical cancer. HPV binding to the cell surface of keratinocytes leads to virus endocytosis at tetraspanin enriched microdomains. Complex interactions of the capsid proteins with host proteins as well as ADAM17-dependent ERK1/2 signal transduction enable the entry platform assembly of the oncogenic HPV type 16. Here, we studied the importance of tetraspanin CD9, also known as TSPAN29, in HPV16 infection of different epithelial cells. We found that both overexpression and loss of the tetraspanin decreased infection rates in cells with low endogenous CD9 levels, while reduction of CD9 expression in keratinocytes that exhibit high-CD9 protein amounts, led to an increase of infection. Therefore, we concluded that low-CD9 supports infection. Moreover, we found that changes in CD9 amounts affect the shedding of the ADAM17 substrate transforming growth factor alpha (TGFα) and the downstream phosphorylation of ERK. These effects correlate with those on infection rates suggesting that a specific CD9 optimum promotes ADAM17 activity, ERK signalling and virus infection. Together, our findings implicate that CD9 regulates HPV16 infection through the modulation of ADAM17 sheddase activity.