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Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity

Abstract

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.

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Fig. 1: TRIM43 is a herpesvirus-specific antiviral factor.
Fig. 2: TRIM43 is induced following herpesvirus infection as part of a DUX4-dependent germline transcriptional program.
Fig. 3: TRIM43 localizes to centrosomes and regulates centrosomal integrity.
Fig. 4: TRIM43 mediates ubiquitination-dependent proteasomal degradation of PCNT.
Fig. 5: Herpesvirus restriction by TRIM43 is dependent on PCNT degradation.
Fig. 6: TRIM43 regulates nuclear lamina integrity and thereby the association of viral chromatin with transcriptionally active host chromatin.

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.

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Acknowledgements

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.

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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.

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Correspondence to Michaela U. Gack.

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Full, F., van Gent, M., Sparrer, K.M.J. et al. Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity. Nat Microbiol 4, 164–176 (2019). https://doi.org/10.1038/s41564-018-0285-5

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