Skip to content

Research at St Andrews

Revisiting promyelocytic leukemia protein targeting by human cytomegalovirus immediate-early protein 1

Research output: Contribution to journalArticlepeer-review


Christina Paulus, Thomas Harwardt, Bernadette Walter, Andrea Marxreiter, Marion Zenger, Edith Reuschel, Michael Martin Nevels

School/Research organisations


Promyelocytic leukemia (PML) bodies are nuclear organelles implicated in intrinsic and innate antiviral defense. The eponymous PML proteins, central to the self-organization of PML bodies, and other restriction factors found in these organelles are common targets of viral antagonism. The 72-kDa immediate-early protein 1 (IE1) is the principal antagonist of PML bodies encoded by the human cytomegalovirus (hCMV). IE1 is believed to disrupt PML bodies by inhibiting PML SUMOylation, while PML was proposed to act as an E3 ligase for IE1 SUMOylation. PML targeting by IE1 is considered to be crucial for hCMV replication at low multiplicities of infection, in part via counteracting antiviral gene induction linked to the cellular interferon (IFN) response. However, current concepts of IE1-PML interaction are largely derived from mutant IE1 proteins known or predicted to be metabolically unstable and globally misfolded. We performed systematic clustered charge-to-alanine scanning mutagenesis and identified a stable IE1 mutant protein (IE1cc172-176) with wild-type characteristics except for neither interacting with PML proteins nor inhibiting PML SUMOylation. Consequently, IE1cc172-176 does not associate with PML bodies and is selectively impaired for disrupting these organelles. Surprisingly, functional analysis of IE1cc172-176 revealed that the protein is hypermodified by mixed SUMO chains and that IE1 SUMOylation depends on nucleosome rather than PML binding. Furthermore, a mutant hCMV expressing IE1cc172-176 was only slightly attenuated compared to an IE1-null virus even at low multiplicities of infection. Finally, hCMV-induced expression of cytokine and IFN-stimulated genes turned out to be reduced rather than increased in the presence of IE1cc172-176 relative to wild-type IE1. Our findings challenge present views on the relationship of IE1 with PML and the role of PML in hCMV replication. This study also provides initial evidence for the idea that disruption of PML bodies upon viral infection is linked to activation rather than inhibition of innate immunity.


Original languageEnglish
Article numbere1008537
Number of pages40
JournalPLoS Pathogens
Issue number5
Publication statusPublished - 4 May 2020

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Evidence for tethering of human cytomegalovirus genomes to host chromosomes

    Mauch-Mücke, K., Schön, K., Paulus, C. & Nevels, M. M., 30 Sep 2020, In: Frontiers in Cellular and Infection Microbiology. 10, 11 p., 577428.

    Research output: Contribution to journalArticlepeer-review

  2. Human cytomegalovirus genomes survive mitosis via the IE19 chromatin-tethering domain

    Lyon, S. M., Yetming, K. D., Paulus, C., Nevels, M., Kalejta, R. F. & Schultz-cherry, S. (ed.), Sep 2020, In: mBio. 11, 5, 17 p., e02410-20.

    Research output: Contribution to journalArticlepeer-review

  3. Revisiting the role of PML protein targeting and disruption of PML bodies in human cytomegalovirus infection

    Paulus, C., Harwardt, T., Walter, B., Marxreiter, A. & Nevels, M. M., 10 Jul 2020, In: Access Microbiology. 2, 7A

    Research output: Contribution to journalArticlepeer-review

  4. Viral DNA binding protein SUMOylation promotes PML nuclear body localization next to viral replication centers

    Stubbe, M., Mai, J., Paulus, C., Stubbe, H. C., Berscheminski, J., Karimi, M., Hofmann, S., Weber, E., Hadian, K., Hay, R., Groitl, P., Nevels, M., Dobner, T. & Schreiner, S., Mar 2020, In: mBio. 11, 2, 21 p., e00049-20.

    Research output: Contribution to journalArticlepeer-review

  5. Human cytomegalovirus pUL83 targets core histones to inhibit interferon synthesis and promote viral spread

    Deb, A., Paulus, C. & Nevels, M. M., 8 Apr 2019, In: Access Microbiology. 1, 1A

    Research output: Contribution to journalArticlepeer-review

Related by journal

  1. PLoS Pathogens (Journal)

    Terry K Smith (Member of editorial board)

    2015 → …

    Activity: Publication peer-review and editorial work typesEditor of research journal

Related by journal

  1. The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

    Young, D. F., Wignall-Fleming, E. B., Busse, D. C., Pickin, M. J., Hankinson, J., Randall, E. M., Tavendale, A., Davison, A. J., Lamont, D., Tregoning, J. S., Goodbourn, S. & Randall, R. E., 11 Feb 2019, In: PLoS Pathogens. 15, 2, 24 p., e1007561.

    Research output: Contribution to journalArticlepeer-review

  2. Branched late-steps of the cytosolic iron-sulphur cluster assembly machinery of Trypanosoma brucei

    Tonini, M. L., Peña-Diaz, P., Haindrich, A. C., Basu, S., Kriegová, E., Pierik, A. J., Lill, R., MacNeill, S. A., Smith, T. K. & Lukeš, J., 22 Oct 2018, In: PLoS Pathogens. 14, 10, 31 p., e1007326.

    Research output: Contribution to journalArticlepeer-review

  3. Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase

    Liu, X-J., Yang, B., Huang, S-N., Wu, C-C., Li, X-J., Cheng, S., Jiang, X., Hu, F., Ming, Y-Z., Nevels, M. M., Britt, W. J., Rayner, S., Tang, Q., Zeng, W-B., Zhao, F. & Luo, M-H., 27 Jul 2017, In: PLoS Pathogens. 13, 7, 28 p., e1006542.

    Research output: Contribution to journalArticlepeer-review

  4. Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

    Harwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Übner, T., Munday, D. C., Nevels, M. & Paulus, C., 7 Jul 2016, In: PLoS Pathogens. 12, 7, 39 p., e1005748.

    Research output: Contribution to journalArticlepeer-review

ID: 268046335