Activation of the Mitochondrial Apoptotic Signaling Platform during Rubella Virus Infection

Claus, Claudia; Manssen, Lena; Hübner, Denise; Roßmark, Sarah; Bothe, Viktoria; Petzold, Alice; Große, Claudia; Reins, Mareen; Mankertz, Annette; Frey, Teryl K.; Liebert, Uwe G.

Cyclophilins act as important co-factors for a number of viruses [28] and are thus a promising target for antiviral countermeasures [29] . Nevertheless, there are also cases in which cyclophilins restrict viral replication [24] . No cellular functions that are vital for RV replication were affected by the application of NIM811 as reflected by the maintained virus production rate. It is important to note that RV specifically affects the expression pattern of the ubiquitous protein Cyp40 that acts as co-chaperone of the Hsp90/Hsp70 complex and guides its interaction with other proteins, including those involved in antiviral host response [30] . Cyp40 is occasionally referred to as CypD, which contributes to some unresolved issues in its physiological functions. Its participation in protein maturation pathways [17] , especially its nuclear localization after stress induction by UVA treatment [31] , heat stress [32] , or RV infection as shown here, certainly warrants further exploration and points to a multitude of physiological functions. Especially heat stress parallels some of the effects exerted by RV on its host cell, including Cyp40 nuclear redistribution and an increase in the Cyp40 mRNA level [32] . Noteworthy in this context is that Hsp90-binding cyclophilins such as Cyp40 are . Proposed model for the involvement of mitochondria-and p53-associated pathways during RV-induced cell death. The transcription-independent mitochondrial p53 function can be blocked by PFTµ. p53 can interact with the pro-apoptotic protein Bax to induce its oligomerization and formation of the mitochondrial apoptosis-induced channel (MAC). The release of pro-apoptotic CytC promotes the formation of the so-called apoptosome consisting of apoptotic protease-activating factor (Apaf-1), pro-caspase 9 and CytC. Effector caspases can be inhibited by the pan-caspase-inhibitor z-VAD-fmk. Application of NIM811 can inhibit cyclophilins such as CypD and Cyp40 as examined in this study. Further explanations are provided in the manuscript. IMS, mitochondrial intermembrane space.