Research Group Florin – Cell biology of human papillomaviruses

Background

Human papillomavirus type 16 (HPV16) is the major causative agent of cervical cancer and contributes to multiple anogenital and head-and-neck malignancies. The Florin laboratory investigates HPV16 entry, morphogenesis, and cellular defense mechanisms. HPV is a non-enveloped DNA tumor virus that infects the skin and mucosa. Our research focuses on a novel clathrin-independent endocytic pathway mediated by tetraspanin-enriched microdomains. We also study MYPOP, a host protein with antiviral activity that suppresses HPV oncogene expression. Beyond its antiviral function, MYPOP appears to have broader tumor-suppressive properties, which we are advancing toward translational applications, including patent development.

Projects

Project 1 – The tetraspanin-mediated endocytosis of HPV

^{HPV16 entry – a multi-step, multi-receptor process. Upper panel: Electron micrographs showing HPV16 associated with CD151 on the cell surface (black dots indicate immunogold labeling). Lower panel: Model of HPV16 entry. Following attachment to primary cell surface receptors, the virus is primed by host proteases and transferred to a secondary receptor complex within tetraspanin-enriched endocytic pits, where it is internalized by clathrin-independent endocytosis.}

We have revealed that HPV16 endocytosis occurs via tetraspanin-enriched microdomains through a novel clathrin- and caveolin-independent entry pathway (Spoden et al., 2008). Specifically, (TIRF) microscopy of live cells, electron microscopy and infection analyses revealed that tetraspanins mediate HPV endocytosis by interaction with laminin-binding integrins, activation of growth factor receptors, and integration of the papillomavirus-receptor complex into cell entry platforms. Our aim is to contribute to a more in depth understanding of the endocytic trafficking pathway that controls HPV entry and infection by building upon novel data that link tetraspanins and its adaptor proteins to HPV infection.

Project 2 – The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic HPV

^{MYPOP suppresses cell growth of cervical cancer cells. Left: MYPOP localization (magenta) in a skin cell; Center: Growth of HPV cancer cells without (top) and with MYPOP (bottom); Right: Tissue section of an HPV tumor (green = MYPOP, blue = cell nuclei).}

Our preliminary data identify MYPOP as a novel HPV-regulated tumor suppressor that is downregulated in HPV-positive cancer cells and inhibits HPV early gene expression, including the viral E7 oncogene. Although MYPOP has therapeutic potential, its molecular interplay with E7 remains unknown. This project will define the tumor-suppressive function of MYPOP, determine how HPV16 E7 promotes its degradation, and identify strategies to prevent this process. We will (i) characterize MYPOP–E7 interactions and MYPOP-associated protein complexes, (ii) elucidate the mechanisms and functional consequences of MYPOP degradation, and (iii) define MYPOP-regulated transcriptional programs using integrated genomic and functional approaches. These studies will establish the role of MYPOP in HPV-associated carcinogenesis and may enable therapeutic strategies to restore MYPOP activity in viral and potentially non-viral cancers.

Selected Publications

Strunk J, Hüppner A, Sial M, Plath M, Sheriff MB, Wagner S, Freitag K, Mikuličić S, Döring T, Bopp T, Klein M, Rajalingam K, Harms G, Marini F, Nedwed AS, Hankeln T, Osterhof C, Schneider MA, Henrich A, Nubbemeyer A, Suchan M, Brill S, Perkovic M, Schrörs B, Kreiter S, Kölsch A, Diken M, Florin L*. The MYB-related transcription factor MYPOP acts as a selective regulator of cancer cell growth. Communications Biology. 2026;9:678. DOI: https://doi.org/10.1038/s42003-026-10272-2
Massenberg A, Homsi Y, Schneider CN, Mikuličić S, Döring T, Florin L*, Lang T*. A rapid transfer of virions coated with heparan sulfate from the ECM to CD151 defines an early step in the human papillomavirus infection cascade. Elife. 2026; doi: https://doi.org/10.7554/eLife.107139
Mikuličić S, Massenberg A, Döring T, Brandenburg K, Lang T, Florin L*. HSPG-binding peptide Pep19-2.5 is a potent inhibitor of HPV16 infection. Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0157524. doi: 10.1128/aac.01575-24. Epub 2025;14.
Mikuličić S, Shamun M, Massenberg A, Franke AL, Freitag K, Döring T, Strunk J, Tenzer S, Lang T, Florin L*. ErbB2/HER2 receptor tyrosine kinase regulates human papillomavirus promoter activity. Front Immunol. 2024;2;15:1335302. doi: 10.3389/fimmu.2024.1335302. eCollection 2024.
Mikuličić S, Finke J, Boukhallouk F, Wüstenhagen E, Sons D, Homsi Y, Reiss K, Lang T, Florin L*; ADAM17-dependent signaling is required for oncogenic Human Papilloma virus entry platform assembly. Elife. 2019;20;8. pii: e44345. doi: 10.7554/eLife.44345.
Guion L, Bienkowska-Haba M, DiGiuseppe S, Florin L, Sapp M; PML nuclear body-residing proteins sequentially associate with HPV genome after infectious nuclear delivery. PLoS Pathog. 2019;25;15(2):e1007590. doi: 10.1371/journal.ppat.1007590. eCollection 2019
Wüstenhagen E, Boukhallouk F, Negwer I, Rajalingam K, Stubenrauch F, Florin L*; The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses. Oncogene. 2018;37(48):6275-6284. doi: 10.1038/s41388-018-0398-6.
Florin L*, Lang T; Tetraspanin Assemblies in Virus Infection. Front Immunol. 2018;25;9:1140. doi: 10.3389/fimmu.2018.01140. eCollection 2018.
Scheffer KD, Gawlitza A, Spoden GA, Zhang XA, Lambert C, Berditchevski F, Florin L*; Tetraspanin CD151 mediates papillomavirus type 16 endocytosis; J Virol. 2013;87(6):3435-46 doi: 10.1128/JVI.02906-12. Epub 2013;9.
Spoden G, Freitag K, Husmann M, Boller K, Sapp M, Lambert C, Florin L*; Clathrin- and caveolin-independent entry of human papillomavirus type 16--involvement of tetraspanin-enriched microdomains (TEMs). PLoS One. 2008;2;3(10):e3313. doi:10.1371/journal.pone.0003313.