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Inhibition of the Secretory Pathway by Foot-and-Mouth Disease Virus 2BC Protein Is Reproduced by Coexpression of 2B with 2C, and the Site of Inhibition Is Determined by the Subcellular Location of 2C

Katy Moffat,¹ Caroline Knox,^2, Gareth Howell,^1, Sarah J. Clark,¹ H. Yang,¹ Graham J. Belsham,^1, Martin Ryan,² and Thomas Wileman^1*

Institute for Animal Health, Pirbright Laboratory, Ash Road, Pirbright, Surrey GU24 0NF, United Kingdom,¹ University of St Andrews, School of Biology, Centre for Biomolecular Sciences, North Haugh, St Andrews KY16 9ST, United Kingdom²

Received 24 February 2006/ Accepted 7 November 2006

Infection of cells with picornaviruses can lead to a block in protein secretion. For poliovirus this is achieved by the 3A protein, and the consequent reduction in secretion of proinflammatory cytokines and surface expression of major histocompatibility complex class I proteins may inhibit host immune responses in vivo. Foot-and-mouth disease virus (FMDV), another picornavirus, can cause persistent infection of ruminants, suggesting it too may inhibit immune responses. Endoplasmic reticulum (ER)-to-Golgi apparatus transport of proteins is blocked by the FMDV 2BC protein. The observation that 2BC is processed to 2B and 2C during infection and that individual 2B and 2C proteins are unable to block secretion stimulated us to study the effects of 2BC processing on the secretory pathway. Even though 2BC was processed rapidly to 2B and 2C, protein transport to the plasma membrane was still blocked in FMDV-infected cells. The block could be reconstituted by coexpression of 2B and 2C, showing that processing of 2BC did not compromise the ability of FMDV to slow secretion. Under these conditions, 2C was located to the Golgi apparatus, and the block in transport also occurred in the Golgi apparatus. Interestingly, the block in transport could be redirected to the ER when 2B was coexpressed with a 2C protein fused to an ER retention element. Thus, for FMDV a block in secretion is dependent on both 2B and 2C, with the latter determining the site of the block.

Published ahead of print on 22 November 2006.

Present address: Rhodes University, Department of Biochemistry, Microbiology and Biotechnology, Grahamstown 6140, South Africa.

Present address: University of Leeds, Institute of Molecular and Cellular Biology, Leeds LS2 9JT, United Kingdom.

Present address: Danish Institute for Food and Veterinary Research, Lindholm, 4771 Kalvehave, Denmark.

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