Kurzfassung

The human papillomavirus (HPV) enters its host cells via an endocytic pathway that is dependent on actin, tetraspanins, and the cytoskeletal adaptor protein Obscurin-Like 1 (OBSL1). Preliminary work demonstrates that these three components co-aggregate at the cell membrane to form an endocytic structure for viral particle uptake, which indicates that OBSL1 is involved early in infection. However, the exact steps and the interactions mediating these steps are unknown. On the other hand, an...The human papillomavirus (HPV) enters its host cells via an endocytic pathway that is dependent on actin, tetraspanins, and the cytoskeletal adaptor protein Obscurin-Like 1 (OBSL1). Preliminary work demonstrates that these three components co-aggregate at the cell membrane to form an endocytic structure for viral particle uptake, which indicates that OBSL1 is involved early in infection. However, the exact steps and the interactions mediating these steps are unknown. On the other hand, an interaction of OBSL1 with the viral particle capsid protein L2 and tubulin points towards a role in late trafficking to the nucleus. Because OBSL1 is a protein with multiple domains, several roles are conceivable - it even could be a central coordinator of the entire trafficking pathway of viral particles.
In this proposal, we aim for unravelling in which steps of the infection pathway OBSL1 is involved, differentiating between viral entry platform formation, membrane invagination, early endosome formation and microtubule dependent transport to the nucleus. For identifying relevant interactions in HPV trafficking, we will study the OBSL1-interactome in non-infected and infected cells. In the main part of the working program, we examine the mechanism that recruits OBSL1 to the cell membrane, which one of its eight domains is required for recruitment, and in which infection step OBSL1 plays a role. Finally, we study more in detail its interactions with L2 and tubulin for clarifying whether OBSL1 indeed is involved in a late trafficking step.  
In conclusion, OBSL1 is an essential factor in HPV infections, but it is not understood how it acts. For examining OBSL1, we will combine our methodological approaches for studying membrane dynamics (Lang lab) and viral infection (Florin lab). We expect gaining deep insights into the nature of OBSL1, what are the interaction partners of this protein, how does it act in the endocytic pathway, and whether it plays a role in later trafficking step of HPV as well. Because it is very unlikely that OBSL1 is only involved in entry of papillomaviruses, the study has general implications for the understanding of viral infections.» weiterlesen» einklappen