Die IRE1-abhängige ER-Stress-Antwort wird durch antagonistische Effekte der Marburg Virus Proteine GP und VP30 ausbalanciert

Marburg virus (MARV) and Ebola virus (EBOV) belong to the family filoviridae. A MARV infection can cause a severe fever disease in humans with a lethality rate of up to 90%. Therefore and as there are no licensed therapeutics or vaccines available against filoviruses, they are classified as biosafety level 4 pathogens. It is essential to characterize the MARV-host interactions to find new targets for therapeutics. Like all viruses MARV depends on the host cell machinery for its replication. For that reason an infection is an additional burden for the cell. The only surface protein of MARV is the glycoprotein GP which is synthesized at the rough ER and folded and glycosylated within the lumen of the endoplasmic reticulum (ER). This process fosters GP to accumulate in the ER before it is transported to the plasma membrane. Previous studies revealed that the ectopic expression of GP overwhelmed the ER (ER stress) and thereby activated the inositol-requiring enzyme 1 α (IRE1)-dependent unfolded protein response (UPR). The active IRE1 splices the X-box binding protein 1 unspliced (XBP1u) mRNA whereby the transcription factor X-box binding protein 1 spliced (XBP1s) is translated. XBP1s binds to the promotors UPR element (UPRE) and ER stress element (ERSE) in the nucleus by what different genes are regulated to restore the ER homeostasis. In contrast prolonged IRE1 activation induces apoptosis. Therefore the UPR can be pro- or antiviral. In this thesis the GP-dependent activation of the UPR was elucidated in detail. The expression of GP activates IRE1, the transcription factor XBP1s as well as the promotor UPRE. GP activates the UPR because of its molecular mass and the many posttranslational modifications, which are mainly located within the mucin-like domain. However, during a MARV infection there is no UPR activation detectable. The reason for that is that the multifunctional viral transcriptionfactor VP30 is able to counteract the IRE1-dependent UPR. Here it was shown for the first time that VP30 interacts RNA-dependent with the XBP1u Protein. XBP1u recruits its own mRNA to the ER membrane to bring it into close proximity to IRE1. Potentially VP30 interacts with the XBP1u mRNA/XBP1u protein complex whereby the XBP1u mRNA is no longer accessible for IRE1. Further experiments showed that the regulation of the UPR is urgent for the MARV replication as either the stimulated - or blocked UPR influences the viral release. Our current knowledge underlines that tight regulations of the UPR are essential for a proper MARV replication which makes it an interesting target for new therapeutics.