SFB 969 TP B02: Deregulation of protein ubiquitylation by human papillomavirus E6 oncoproteins

Beschreibung

Since the coding capacity of viral genomes is rather limited, it is essential for viruses to reprogram the host cell metabolism according to viral need. This type of adaption can be achieved by various means including modulation of host cell gene expression and exploitation of host cell regulatory proteins. Thus, in-depth analysis of viral regulatory proteins and their effect on host cell metabolism provides an attractive opportunity to obtain insight into mechanisms and processes governing cellular proteostasis. A prominent example is provided by the E6 oncoproteins of cancer-associated "high risk" human papillomaviruses (HPVs) that inactivate the tumor suppressor p53 by utilizing the cellular ubiquitin ligase E6AP. In contrast to high risk E6 proteins, E6 proteins of "low risk" HPVs that are not associated with cancer do not target p53 for degradation. However, we recently showed that low risk E6 proteins do have the ability to functionally interact with E6AP. Thus, the main working hypothesis of this proposal is that both low risk and high risk E6 proteins utilize E6AP to target yet unknown host proteins for ubiquitylation and degradation. Furthermore, there is data to suggest that E6AP is not only utilized by E6 but in addition, represents itself a target for the E6 proteins (i.e. binding of E6 interferes with the normal functions of E6AP). To address these questions, we propose to employ various approaches including inducible protein expression, affinity chromatography, and mass spectrometry to identify substrate proteins and interaction partners of the E6 proteins and to determine the effect of the E6 proteins on the cellular proteome in the presence or absence of E6AP. The proposed studies will (1) contribute to the identification of cellular pathways that are targeted by the E6 proteins of low risk and high risk HPVs and may thus be of significance for virus-induced cellular transformation and/or viral propagation and (2) reveal if the E6 proteins interfere with normal cellular functions of E6AP.

Institutionen
  • FB Biologie
Mittelgeber
NameKennzifferBeschreibungLaufzeit
SFB922/11keine Angabe
Weitere Informationen
Laufzeit: 01.01.2012 – 31.12.2019