TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6.

Autor: Zhao Y; Department of Pathology, University of Cambridge, Cambridge, UK.; Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Lu Y; Department of Pathology, University of Cambridge, Cambridge, UK.; Sir William Dunn School of Pathology, University of Oxford, Oxford, UK., Richardson S; The Pirbright Institute, Surrey, UK., Sreekumar M; Department of Pathology, University of Cambridge, Cambridge, UK., Albarnaz JD; Department of Pathology, University of Cambridge, Cambridge, UK. jd732@cam.ac.uk.; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. jd732@cam.ac.uk., Smith GL; Department of Pathology, University of Cambridge, Cambridge, UK. geoffrey.smith@path.ox.ac.uk.; Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. geoffrey.smith@path.ox.ac.uk.; The Pirbright Institute, Surrey, UK. geoffrey.smith@path.ox.ac.uk.; Chinese Academy of Medical Sciences-Oxford Institute, University of Oxford, Oxford, UK. geoffrey.smith@path.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Aug; Vol. 620 (7975), pp. 873-880. Date of Electronic Publication: 2023 Aug 09.
DOI: 10.1038/s41586-023-06401-0
Abstrakt: Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV 1-5 ; however, reports are limited for DNA viruses 6,7 . Here we demonstrate that TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds to the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, the protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola.
(© 2023. The Author(s).)
Databáze: MEDLINE
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