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J Biol Chem. 2007 Jul 13;282(28):20774-84. Epub 2007 May 8.

Infectious bursal disease virus, a non-enveloped virus, possesses a capsid-associated peptide that deforms and perforates biological membranes.

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Unité de Virologie et Immunologie Moléculaires, UR892, Batiment de Biotechnologies, Institut National de la Recherche Agronomique, Domaine de Vilvert, 78350 Jouy-en-Josas, France.


Double-stranded RNA (dsRNA) virions constitute transcriptionally competent machines that must translocate across cell membranes to function within the cytoplasm. The entry mechanism of such non-enveloped viruses is not well described. Birnaviruses are unique among dsRNA viruses because they possess a single shell competent for entry. We hereby report how infectious bursal disease virus, an avian birnavirus, can disrupt cell membranes and enter into its target cells. One of its four structural peptides, pep46 (a 46-amino acid amphiphilic peptide) deforms synthetic membranes and induces pores visualized by electron cryomicroscopy, having a diameter of less than 10 nm. Using both biological and synthetic membranes, the pore-forming domain of pep46 was identified as its N terminus moiety (pep22). The N and C termini of pep22 are shown to be accessible during membrane destabilization and pore formation. NMR studies show that pep46 inserted into micelles displays a cis-trans proline isomerization at position 16 that we propose to be associated to the pore formation process. Reverse genetic experiments confirm that the amphiphilicity and proline isomerization of pep46 are both essential to the viral cycle. Furthermore, we show that virus infectivity and its membrane activity (probably because of the release of pep46 from virions) are controlled differently by calcium concentration, suggesting that entry is performed in two steps, endocytosis followed by endosome permeabilization. Our findings reveal a possible entry pathway of infectious bursal disease virus: in endosomes containing viruses, the lowering of the calcium concentration promotes the release of pep46 that induces the formation of pores in the endosomal membrane.

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