Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi’s sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43–pericentrin–lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. RNA–seq data from this study are deposited in NCBI GEO under accession code GSE101435. Supplementary figures and tables are available in the Supplementary Information. Complete western blot images of all figures in the manuscript are provided in Supplementary Fig. 11.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Corey, L. & Wald, A. Maternal and neonatal herpes simplex virus infections. N. Engl. J. Med. 361, 1376–1385 (2009).

  2. 2.

    Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878–889 (2010).

  3. 3.

    Dittmer, D. P. & Damania, B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J. Clin. Invest. 126, 3165–3175 (2016).

  4. 4.

    Ozato, K., Shin, D. M., Chang, T. H. & Morse, H. C. 3rd TRIM family proteins and their emerging roles in innate immunity. Nat. Rev. Immunol. 8, 849–860 (2008).

  5. 5.

    Rajsbaum, R., Garcia-Sastre, A. & Versteeg, G. A. TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J. Mol. Biol. 426, 1265–1284 (2014).

  6. 6.

    Bernardi, R. & Pandolfi, P. P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat. Rev. Mol. Cell Biol. 8, 1006–1016 (2007).

  7. 7.

    Scherer, M. & Stamminger, T. Emerging role of PML nuclear bodies in innate immune signaling. J. Virol. 90, 5850–5854 (2016).

  8. 8.

    Vieira, J. & O’Hearn, P. M. Use of the red fluorescent protein as a marker of Kaposi’s sarcoma-associated herpesvirus lytic gene expression. Virology 325, 225–240 (2004).

  9. 9.

    Duggal, N. K. & Emerman, M. Evolutionary conflicts between viruses and restriction factors shape immunity. Nat. Rev. Immunol. 12, 687–695 (2012).

  10. 10.

    Kim, J., Tipper, C. & Sodroski, J. Role of TRIM5α RING domain E3 ubiquitin ligase activity in capsid disassembly, reverse transcription blockade, and restriction of simian immunodeficiency virus. J. Virol. 85, 8116–8132 (2011).

  11. 11.

    Gack, M. U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

  12. 12.

    Carthagena, L. et al. Human TRIM gene expression in response to interferons. PLoS ONE 4, e4894 (2009).

  13. 13.

    Desmyter, J., Melnick, J. L. & Rawls, W. E. Defectiveness of interferon production and of rubella virus interference in a line of African green monkey kidney cells (Vero). J. Virol. 2, 955–961 (1968).

  14. 14.

    Stanghellini, I., Falco, G., Lee, S. L., Monti, M. & Ko, M. S. Trim43a, Trim43b, and Trim43c: novel mouse genes expressed specifically in mouse preimplantation embryos. Gene Expr. Patterns 9, 595–602 (2009).

  15. 15.

    Hendrickson, P. G. et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. 49, 925–934 (2017).

  16. 16.

    De Iaco, A. et al. DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat. Genet. 49, 941–945 (2017).

  17. 17.

    Whiddon, J. L., Langford, A. T., Wong, C. J., Zhong, J. W. & Tapscott, S. J. Conservation and innovation in the DUX4-family gene network. Nat. Genet. 49, 935–940 (2017).

  18. 18.

    Geng, L. N. et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev. Cell 22, 38–51 (2012).

  19. 19.

    Lemmers, R. J. et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329, 1650–1653 (2010).

  20. 20.

    Ferreboeuf, M. et al. DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Hum. Mol. Genet. 23, 171–181 (2014).

  21. 21.

    Daxinger, L., Tapscott, S. J. & van der Maarel, S. M. Genetic and epigenetic contributors to FSHD. Curr. Opin. Genet. Dev. 33, 56–61 (2015).

  22. 22.

    Doxsey, S. J., Stein, P., Evans, L., Calarco, P. D. & Kirschner, M. Pericentrin, a highly conserved centrosome protein involved in microtubule organization. Cell 76, 639–650 (1994).

  23. 23.

    Dictenberg, J. B. et al. Pericentrin and γ-tubulin form a protein complex and are organized into a novel lattice at the centrosome. J. Cell Biol. 141, 163–174 (1998).

  24. 24.

    Schockel, L., Mockel, M., Mayer, B., Boos, D. & Stemmann, O. Cleavage of cohesin rings coordinates the separation of centrioles and chromatids. Nat. Cell Biol. 13, 966–972 (2011).

  25. 25.

    Starr, D. A. A nuclear-envelope bridge positions nuclei and moves chromosomes. J. Cell Sci. 122, 577–586 (2009).

  26. 26.

    Gruenbaum, Y., Margalit, A., Goldman, R. D., Shumaker, D. K. & Wilson, K. L. The nuclear lamina comes of age. Nat. Rev. Mol. Cell Biol. 6, 21–31 (2005).

  27. 27.

    Verstraeten, V. L. et al. Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect. Proc. Natl Acad. Sci. USA 108, 4997–5002 (2011).

  28. 28.

    Gundersen, G. G. & Worman, H. J. Nuclear positioning. Cell 152, 1376–1389 (2013).

  29. 29.

    Pasdeloup, D., Labetoulle, M. & Rixon, F. J. Differing effects of herpes simplex virus 1 and pseudorabies virus infections on centrosomal function. J. Virol. 87, 7102–7112 (2013).

  30. 30.

    Silva, L., Cliffe, A., Chang, L. & Knipe, D. M. Role for A-type lamins in herpesviral DNA targeting and heterochromatin modulation. PLoS Pathog. 4, 1000071 (2008).

  31. 31.

    Ma, H. et al. Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow. Nat. Biotechnol. 34, 528–530 (2016).

  32. 32.

    Ressing, M. E. et al. Impaired transporter associated with antigen processing-dependent peptide transport during productive EBV infection. J. Immunol. 174, 6829–6838 (2005).

  33. 33.

    Marquitz, A. R., Mathur, A., Shair, K. H. Y. & Raab-Traub, N. Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression. Proc. Natl Acad. Sci. USA 109, 9593–9598 (2012).

  34. 34.

    Chan, Y. K. & Gack, M. U. A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity. Nat. Immunol. 17, 523–530 (2016).

  35. 35.

    Snider, L. et al. RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum. Mol. Genet. 18, 2414–2430 (2009).

  36. 36.

    Pauli, E. K. et al. The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25. Sci. Signal. 7, 2004577 (2014).

  37. 37.

    Kim, J., Lee, K. & Rhee, K. PLK1 regulation of PCNT cleavage ensures fidelity of centriole separation during mitotic exit. Nat. Commun. 6, 10076 (2015).

  38. 38.

    Kim, S. & Rhee, K. Importance of the CEP215-pericentrin ineraction for centrosome maturation during mitosis. PLoS ONE 9, e87016 (2014).

  39. 39.

    Reed, L. J. & Muench, H. A simple method of estimating fifty per cent endpoints. Am. J. Epidemiol. 27, 493–497 (1938).

  40. 40.

    Lorz, K. et al. Deletion of open reading frame UL26 from the human cytomegalovirus genome results in reduced viral growth, which involves impaired stability of viral particles. J. Virol. 80, 5423–5434 (2006).

  41. 41.

    Andreoni, M., Faircloth, M., Vugler, L. & Britt, W. J. A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. J. Virol. Methods 23, 157–167 (1989).

  42. 42.

    Full, F. et al. Kaposi’s sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog. 10, e1003863 (2014).

  43. 43.

    Afgan, E. et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res. 44, W3–W10 (2016).

  44. 44.

    Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, 10–12 (2011).

  45. 45.

    Andrews, S. FastQC: A Quality Control Tool for High Throughput Sequence Data (2017); https://www.bioinformatics.babraham.ac.uk/projects/fastqc/

  46. 46.

    Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).

  47. 47.

    Dillies, M. A. et al. A comprehensive evaluation of normalization methods for Illumina high-throughput RNA sequencing data analysis. Brief. Bioinform. 14, 671–683 (2013).

  48. 48.

    R Core Team. A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2013).

  49. 49.

    Naschberger, E. et al. Matricellular protein SPARCL1 regulates tumor microenvironment-dependent endothelial cell heterogeneity in colorectal carcinoma. J. Clin. Invest. 126, 4187–4204 (2016).

Download references


The authors thank M. Ericsson from the Harvard Electron Microscopy Facility, Boston, for assistance with sample preparation and electron microscopy, and R. Tomaino (Taplin Mass Spectrometry Facility, Harvard) for mass spectrometry analysis. The authors also thank G. Förtsch (Division of Molecular and Experimental Surgery, University Hospital Erlangen) for excellent technical assistance and R. Coras (Department of Neuropathology, University Hospital Erlangen) for cerebellum tissue used as a staining control. This study was supported by the US National Institutes of Health grants R21 AI118509, R01 AI087846 and R01 AI127774 (to M.U.G.), and grants from the German Research Foundation CRC796, TP B1 and EN423/5-1 (to A.E.), CRC796 and STA357/7-1 (to T.S.), FOR 2438/subproject 2 (to M.St.), FU 949/1-1 and FU 949/2-1 (to F.F.) and SP 1600/1-1 (to K.M.J.S.). F.F. was further supported by a Marie Skłodowska-Curie Individual Fellowship from the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under grant agreement no. 703896, and the Interdisciplinary Center for Clinical Research Erlangen (IZKF, J57). M.A.Z. received support from NIH training grant T32 GM007183. A.E. also received funding from IZKF, A66.

Author information


  1. Department of Microbiology, The University of Chicago, Chicago, IL, USA

    • Florian Full
    • , Michiel van Gent
    • , Konstantin M. J. Sparrer
    • , Cindy Chiang
    • , Matthew A. Zurenski
    •  & Michaela U. Gack
  2. Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany

    • Florian Full
    • , Klaus Korn
    •  & Armin Ensser
  3. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany

    • Konstantin M. J. Sparrer
  4. Institute of Virology, Ulm University Medical Center, Ulm, Germany

    • Myriam Scherer
    •  & Thomas Stamminger
  5. Department of Dermatology, Venerology, and Allergology, Center for Sexual Health and Medicine, Ruhr University Bochum, Bochum, Germany

    • Norbert H. Brockmeyer
  6. Department of Dermatology, University Hospital Erlangen, Erlangen, Germany

    • Lucie Heinzerling
  7. Division of Molecular and Experimental Surgery, Department of Surgery, University Hospital Erlangen, Erlangen, Germany

    • Michael Stürzl


  1. Search for Florian Full in:

  2. Search for Michiel van Gent in:

  3. Search for Konstantin M. J. Sparrer in:

  4. Search for Cindy Chiang in:

  5. Search for Matthew A. Zurenski in:

  6. Search for Myriam Scherer in:

  7. Search for Norbert H. Brockmeyer in:

  8. Search for Lucie Heinzerling in:

  9. Search for Michael Stürzl in:

  10. Search for Klaus Korn in:

  11. Search for Thomas Stamminger in:

  12. Search for Armin Ensser in:

  13. Search for Michaela U. Gack in:


F.F. and M.U.G. designed the experiments and wrote the manuscript. F.F., M.v.G., K.M.J.S., C.C., M.A.Z. and M.Sc. performed experiments and analysed data. N.H.B., L.H. and M.St. provided KS tissue samples. K.K. provided BAL samples. A.E., T.S. and M.St. supervised aspects of this study. M.U.G. was responsible for the overall conception and supervision of the study.

Competing interests

The authors declare no competing interest.

Corresponding author

Correspondence to Michaela U. Gack.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–11, Supplementary Table 1.

  2. Reporting Summary

About this article

Publication history