Foot-and-mouth disease virus 3C protease induces fragmentation of the Golgi compartment and blocks intra-Golgi transport.

Zhigang Zhou,Stephen Curry,Mette M Mogensen,Thomas Wileman,Penny P Powell

doi:10.1128/jvi.01355-13

Zhigang Zhou, Stephen Curry + Show 3 more

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https://doi.org/10.1128/jvi.01355-13

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Abstract

Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines. In this study, we show that Golgi fragmentation and a block in secretion are induced by expression of foot-and-mouth disease virus (FMDV) 3Cpro and that this requires the protease activity of 3Cpro. 3Cpro caused fragmentation of early, medial, and late Golgi compartments, but the most marked effect was on early Golgi compartments, indicated by redistribution of ERGIC53 and membrin. Golgi fragments were dispersed in the cytoplasm and were able to receive a model membrane protein exported from the endoplasmic reticulum (ER). Golgi fragments were, however, unable to transfer the protein to the plasma membrane, indicating a block in intra-Golgi transport. Golgi fragmentation was coincident with a loss of microtubule organization resulting from an inhibition of microtubule regrowth from the centrosome. Inhibition of microtubule regrowth also required 3Cpro protease activity. The loss of microtubule organization induced by 3Cpro caused Golgi fragmentation, but loss of microtubule organization does not block intra-Golgi transport. It is likely that the block of intra-Golgi transport is imposed by separate actions of 3Cpro, possibly through degradation of proteins required for intra-Golgi transport.

Highlights

Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines
The effect of an inactive form of 3C protease (3Cpro) on the Golgi compartment was tested by expression of an enzyme where cysteine 163 in the active site had been converted to alanine (Fig. 1A)
In the presence of inactive 3C protease (Fig. 1A, i), ERGIC53 was distributed within a series of vesicles mostly localized to one side of the nucleus (Fig. 1A, ii), and a similar distribution was seen for ␤-COP (Fig. 1A, vii)

Summary

Introduction

Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines. The vesicles contain newly synthesized viral RNA and are thought to facilitate replication and/or shield virus genomes from recognition by cellular helicases such as Rig and MDA5, both of which can initiate interferon responses This remodeling of ER and Golgi membranes is coincident with a block in the secretory pathway which is thought to provide further protection from immune surveillance. The importance of the block in secretion in the context of immune evasion has led to a search for picornavirus proteins that inhibit the secretory pathway when expressed alone or in combination in cells Up until now, these studies have focused on proteins such as 2B, 2BC, 2C, and 3A, all of which have membranebinding motifs and associate with membrane vesicles induced during infection. We have shown previously [21] that 3Cpro of FMDV causes loss of tubulin organization and disruption of the micro-

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