Myriam Scherer

Suche


B3 Interference of the viral effector proteins pp71 and IE1 with ND10-mediated intrinsic immunity against human cytomegalovirus infections

Principal investigator
Thomas Stamminger

Mentor
Yves Muller

PhD exam: 24.05.2013

Antagonisation of cellular antiviral mechanisms mediated by the human cytomegalovirus protein IE1

Infection with human cytomegalovirus (HCMV), a member of the beta-herpesvirus subfamily, results in the association of viral genomes and replication factors with a cellular subnuclear structure called nuclear domain 10 (ND10). ND10-domains are aggregations of multiple cellular proteins that require the PML protein for their formation. It has been shown that ND10-domains mediate an intrinsic defense mechanism against herpesviral infections, which is antagonized by the viral regulatory protein IE1. During infection, IE1 initially targets to ND10-sites and afterwards induces the disruption of these structures. It was proposed that the dispersal of ND10 components is caused by IE1-mediated de-SUMOylation of PML, as only SUMOylated PML can organise the ND10 formation. However, it is unclear how IE1 leads to the abrogation of PML-SUMOylation. Moreover, HCMV infection of PML knock-down cells, which usually show a diffuse pattern of ND10 components, induces the accumulation of ND10 proteins. Since IE1 can disrupt these ND10-like structures in the absence of PML, IE1-mediated dissociation of ND10-domains cannot solely be explained by the de-SUMOylation of PML.
This project aims for a detailed characterisation of the mechanisms used by IE1 to counteract the repressive effects of ND10. The IE1-mediated de-SUMOylation of PML will be investigated by characterizing interactions of IE1 with SUMO-proteases. Moreover, we want to identify further target proteins that interact with IE1 or are de-SUMOylated in the prescence of IE1. Additionally, the three-dimensional structure of IE1 will be determined by protein crystallisation, as this could give information about the molecular interactions of IE1 with host cell factors.

Figure: Subcellular localization of IE1 and the ND10 component PML in HFFs at 2h or 4h after infection with HCMV strain AD169 and in control fibroblasts.

 

Publications

Scherer, M., Reuter, N., Wagenknecht, N., Otto, V., Sticht, H. and Stamminger, T.(2013).SUMO pathway-mediated enhancement of human cytomegalovirus replication correlates with a recruitment of SUMO-1/3 proteins to viral replication compartments. J Gen Virol 94, 1373-1884.

Tavalai, N., Adler, M., Scherer, M., Riedl, Y. and Stamminger, T. (2011). Evidence for a dual antiviral role of the major nuclear domain 10 component Sp100 during the immediate-early and late phases of the human cytomegalovirus replication cycle. J Virol 85(18), 9447-9458.

 

Presentations

March 2013 23rd Annual Meeting of the Society for Virology, Kiel, Germany
Insights into structural determinants for nuclear domain 10 disruption by the IE1 protein of human cytomegalovirus
Talk
     
August 2012 37th Annual Herpesvirus Workshop, Calgary, Canada
Insights into the structural determinants for nuclear domain 10 disruption by the major immediate early protein IE1 of primate cytomegaloviruses
Poster
     
July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Insights into the structural determinants for nuclear domain 10 disruption by the major immediate-early protein IE1 of primate cytomegaloviruses
Talk and Poster
     
June 2012 International Symposium: Fourty Years of Virology at the University of Erlangen-Nürnberg, Erlangen, Germany
Insights into the structural determinants for nuclear domain 10 disruption by the major immediate early protein IE1 of primate cytomegaloviruses
Poster
     
March 2012 22nd Annual Meeting of the Society for Virology, Essen, Germany
Crystallization, preliminary structure determination and functional characterization of the major immediate early protein IE1 of primate cytomegaloviruses
Talk
     
October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
SUMO proteins are recruited to viral replication compartments and promote human cytomegalovirus replication
Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Antagonization of ND10-mediated intrinsic immunity by the human cytomegalovirus protein IE1
Talk and Poster
     
July 2011 36th Annual International Herpesvirus Workshop, Gdansk, Poland
SUMO proteins are recruited to viral replication compartments and promote human cytomegalovirus replication
Poster
     
May 2011 13th International CMV/BetaHerpesvirus Workshop, Nuremberg, Germany
SUMO proteins are recruited to viral replication compartments and promote human cytomegalovirus replication
Poster
     
March 2011 21st Annual Meeting of the Society for Virology, Freiburg, Germany
SUMO proteins are recruited to viral replication compartments and promote human cytomegalovirus replication
Poster
     
January 2011 Methods in Molecular Virology, Institute of Virology, Erlangen, Germany
The IE1 Protein of Human Cytomegalovirus as an Antagonist of ND10-mediated Intrinsic Immunity - Purification and Crystallization of IE1
Talk
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
The IE1 Protein of Human Cytomegalovirus as an Antagonist of ND10-mediated Intrinsic Immunity
Talk
     

 

Awards

Best Talk Award
4th Annual Retreat, Erlangen School of Molecular Communication
Kloster Banz, Bad Staffelstein, Germany, July 2012
Insights into the structural determinants for nuclear domain 10 disruption by the major immediate-early protein IE1 of primate cytomegaloviruses