Interference of the viral effector proteins pp71 and IE1 with intrinsic and innate immunity against human cytomegalovirus infections

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The cytomegaloviral regulatory proteins pp71 and IE1 have previously been shown to modify a cellular subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies. ND10 represent discrete interchromosomal accumulations of multiple cellular factors including hDaxx, Sp100 or SUMO that require the PML protein for their formation and act as key mediators of intrinsic immunity against human cytomegalovirus and other viruses. While pp71 interacts with hDaxx/ATRX, IE1 was shown to bind to PML resulting in protein deSUMOylation. Highlight of our previous work was the finding, that the crystal structure of the cytomegalovirus IE1 protein shares significant homology to the coiled-coil domain of TRIM proteins. Consequently, we could show that IE1 binds to the coiled-coil domain of PML (=TRIM19) and also other TRIM proteins like TRIM5alpha and TRIM33. Furthermore, we could demonstrate that PML plays a novel co-regulatory role in type-I and type-II interferon-induced gene expression which is antagonized via the binding of IE1. In summary, these result suggest that IE1 not only modulates functions of TRIM19 (= PML) in intrinsic and innate immunity but also affects additional members of this protein family. Since the E3 ligase TRIM family of proteins is implicated to regulate multiple signaling pathways triggered by innate immune-pattern-recognition receptors, we are interested to define in detail which TRIM proteins are modulated by IE1. Furthermore, the exact mode of interaction between IE1 and the coiled-coil structures of specific TRIM proteins is still unclear. This will be investigated by co-crystallization and by crosslinking studies. Based on detailed knowledge of the interaction mode we plan to search for peptides and substances that block IE1 function and thus act antiviral. Furthermore, we detected that not only IE1 but also pp71 binds to specific TRIM proteins, which will also be investigated during this project. Overall, the proposed project will foster our understanding how multifunctional viral proteins like IE1 and pp71 are able to evade intrinsic and innate immune mechanisms governed by TRIM factors.