Sec62 Regulates Endoplasmic Reticulum Stress and Autophagy Balance to Affect Foot-and-Mouth Disease Virus Replication

Endoplasmic reticulum (ER) stress-induced autophagy is closely associated with viral infection and propagation. However, the intrinsic link between ER stress, autophagy, and viral replication during foot-and-mouth disease virus (FMDV) infection is not fully elucidated. Our previous studies demonstrated that FMDV infection activated the ER stress-associated UPR of the PERK-eIF2a and ATF6 signaling pathway, whereas the IRE1a signaling was suppressed. We found that the activated-ATF6 pathway participated in FMDV-induced autophagy and FMDV replication, while the IRE1α pathway only affected FMDV replication. Further studies indicated that Sec62 was greatly reduced in the later stages of FMDV infection and blocked the activation of the autophagy-related IRE1α-JNK pathway. Moreover, it was also found that Sec62 promoted IRE1a phosphorylation and negatively regulated FMDV proliferation. Importantly, Sec62 may interact with LC3 to regulate ER stress and autophagy balance and eventually contribute to FMDV clearance via fusing with lysosomes. Altogether, these results suggest that Sec62 is a critical molecule in maintaining and recovering ER homeostasis by activating the IRE1α-JNK pathway and delivering autophagosome into the lysosome, thus providing new insights on FMDV-host interactions and novel antiviral therapies.

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A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection

Journal of General Virology ◽

10.1099/vir.0.055442-0 ◽

2013 ◽

Vol 94 (12) ◽

pp. 2636-2646 ◽

Cited By ~ 19

Author(s):

Rebecca Midgley ◽

Katy Moffat ◽

Stephen Berryman ◽

Philippa Hawes ◽

Jennifer Simpson ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Disease Virus ◽

Secretory Pathway ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Rab Proteins ◽

Fmdv Infection ◽

Early Secretory Pathway ◽

Mouth Disease Virus ◽

Foot And Mouth

Picornaviruses replicate their genomes in association with cellular membranes. While enteroviruses are believed to utilize membranes of the early secretory pathway, the origin of the membranes used by foot-and-mouth disease virus (FMDV) for replication are unknown. Secretory-vesicle traffic through the early secretory pathway is mediated by the sequential acquisition of two distinct membrane coat complexes, COPII and COPI, and requires the coordinated actions of Sar1, Arf1 and Rab proteins. Sar1 is essential for generating COPII vesicles at endoplasmic reticulum (ER) exit sites (ERESs), while Arf1 and Rab1 are required for subsequent vesicle transport by COPI vesicles. In the present study, we have provided evidence that FMDV requires pre-Golgi membranes of the early secretory pathway for infection. Small interfering RNA depletion of Sar1 or expression of a dominant-negative (DN) mutant of Sar1a inhibited FMDV infection. In contrast, a dominant-active mutant of Sar1a, which allowed COPII vesicle formation but inhibited the secretory pathway by stabilizing COPII coats, caused major disruption to the ER–Golgi intermediate compartment (ERGIC) but did not inhibit infection. Treatment of cells with brefeldin A, or expression of DN mutants of Arf1 and Rab1a, disrupted the Golgi and enhanced FMDV infection. These results show that reagents that block the early secretory pathway at ERESs have an inhibitory effect on FMDV infection, while reagents that block the early secretory pathway immediately after ER exit but before the ERGIC and Golgi make infection more favourable. Together, these observations argue for a role for Sar1 in FMDV infection and that initial virus replication takes place on membranes that are formed at ERESs.

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Proteomics Analysis of Porcine Serum Proteins by LC-MS/MS after Foot-and-Mouth Disease Virus (FMDV) Infection

Journal of Veterinary Medical Science ◽

10.1292/jvms.11-0019 ◽

2011 ◽

Vol 73 (12) ◽

pp. 1569-1572 ◽

Cited By ~ 7

Author(s):

Yongjie LIU ◽

Keshan ZHANG ◽

Haixue ZHENG ◽

Youjun SHANG ◽

Jianhong GUO ◽

...

Keyword(s):

Disease Virus ◽

Serum Proteins ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Proteomics Analysis ◽

Porcine Serum ◽

Fmdv Infection ◽

Mouth Disease Virus ◽

Foot And Mouth

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Establishment of persistent foot-and-mouth disease virus (FMDV) infection in MDBK cells

Archives of Virology ◽

10.1007/s00705-015-2526-8 ◽

2015 ◽

Vol 160 (10) ◽

pp. 2503-2516 ◽

Cited By ~ 7

Author(s):

Lela Kopliku ◽

Anthony Relmy ◽

Aurore Romey ◽

Kamila Gorna ◽

Stephan Zientara ◽

...

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Fmdv Infection ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Mdbk Cells

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Lithium chloride inhibits early stages of foot-and-mouth disease virus (FMDV) replication in vitro

Journal of Medical Virology ◽

10.1002/jmv.24821 ◽

2017 ◽

Vol 89 (11) ◽

pp. 2041-2046 ◽

Cited By ~ 15

Author(s):

Fu-Rong Zhao ◽

Yin-Li Xie ◽

Ze-Zhong Liu ◽

Jun-Jun Shao ◽

Shi-Fang Li ◽

...

Keyword(s):

Disease Virus ◽

Lithium Chloride ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Early Stages ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

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The DDX23 Negatively Regulates Translation and Replication of Foot-and-Mouth Disease Virus and Is Degraded by 3C Proteinase

Viruses ◽

10.3390/v12121348 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1348

Author(s):

Sahibzada Waheed Abdullah ◽

Shichong Han ◽

Jin’en Wu ◽

Yun Zhang ◽

Manyuan Bai ◽

...

Keyword(s):

Disease Virus ◽

Small Interfering Rna ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Dependent Manner ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Rna Knockdown ◽

Interfering Rna ◽

Fmdv Replication

DEAD-box helicase 23 (DDX23) is a host nuclear helicase, which is a part of the spliceosomal complex and involved in pre-mRNA splicing. To investigate whether DDX23, an internal ribosomal entry sites transacting factor (ITAF) affects foot-and-mouth disease virus (FMDV) replication and translation through internal ribosome entry site (IRES)-dependent manner. For this, we utilized a pull-down assay, Western blotting, quantitative real-time PCR, confocal microscopy, overexpression and small interfering RNA knockdown, as well as the median tissue culture infective dose. Our findings showed that FMDV infection inhibited DDX23 expression and the overexpression of DDX23 reduced viral replication, however, CRISPR Cas9 knockout/small interfering RNA knockdown increased FMDV replication. FMDV IRES domain III and IV interacted with DDX23, whereas DDX23 interacted with FMDV 3C proteinase and significantly degraded. The enzymatic activity of FMDV 3C proteinase degraded DDX23, whereas FMDV degraded DDX23 via the lysosomal pathway. Additionally, IRES-driven translation was suppressed in DDX23-overexpressing cells, and was enhanced in DDX23 knocked down. Collectively, our results demonstrated that DDX23 negatively affects FMDV IRES-dependent translation, which could be a useful target for the design of antiviral drugs.

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Basal Level p53 Suppresses Antiviral Immunity against Foot-and-Mouth Disease Virus

Viruses ◽

10.3390/v11080727 ◽

2019 ◽

Vol 11 (8) ◽

pp. 727

Author(s):

Zhang ◽

Chen ◽

Liu ◽

Qi ◽

Gao ◽

...

Keyword(s):

Innate Immunity ◽

Disease Virus ◽

Knockout Mice ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Clear Cut ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Immune Related Genes ◽

Fmdv Replication

Tumor suppressor protein p53 (p53) is a master transcription factor that plays key roles in cell cycle arrest, apoptosis, senescence, and metabolism, as well as regulation of innate immunity during virus infection. In order to facilitate their replication and spreading, viruses have evolved to manipulate p53 function through different strategies, with some requiring active p53 while others demand reduction/inhibition of p53 activity. However, there are no clear-cut reports about the roles of p53 during the infection of foot-and-mouth disease virus (FMDV), the causative agent of a highly contagious foot-and-mouth disease (FMD) of cloven-hoofed animals. Here we showed that p53 level was dynamically regulated during FMDV infection, being degraded at the early infection stage but recovered to the basal level at the late stage. Cells depleted of p53 showed inhibited FMDV replication and enhanced expression of the immune-related genes, whereas overexpression of p53 didn’t affect the viral replication. Viral challenge assay with p53 knockout mice obtained similar results, with viral load decreased, histopathological changes alleviated, and lifespan extended in the p53 knockout mice. Together, these data demonstrate that basal level p53 is required for efficient FMDV replication by suppressing the innate immunity.

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The Carrier Conundrum; A Review of Recent Advances and Persistent Gaps Regarding the Carrier State of Foot-and-Mouth Disease Virus

Pathogens ◽

10.3390/pathogens9030167 ◽

2020 ◽

Vol 9 (3) ◽

pp. 167 ◽

Cited By ~ 2

Author(s):

Carolina Stenfeldt ◽

Jonathan Arzt

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Field Studies ◽

Carrier State ◽

Mouth Disease ◽

Experimental Investigations ◽

Apparent Lack ◽

Fmdv Infection ◽

Mouth Disease Virus ◽

Foot And Mouth

The existence of a prolonged, subclinical phase of foot-and-mouth disease virus (FMDV) infection in cattle was first recognized in the 1950s. Since then, the FMDV carrier state has been a subject of controversy amongst scientists and policymakers. A fundamental conundrum remains in the discordance between the detection of infectious FMDV in carriers and the apparent lack of contagiousness to in-contact animals. Although substantial progress has been made in elucidating the causal mechanisms of persistent FMDV infection, there are still critical knowledge gaps that need to be addressed in order to elucidate, predict, prevent, and model the risks associated with the carrier state. This is further complicated by the occurrence of a distinct form of neoteric subclinical infection, which is indistinguishable from the carrier state in field scenarios, but may have substantially different epidemiological properties. This review summarizes the current state of knowledge of the FMDV carrier state and identifies specific areas of research in need of further attention. Findings from experimental investigations of FMDV pathogenesis are discussed in relation to experience gained from field studies of foot-and-mouth disease.

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The Kinase STK3 Interacts with the Viral Structural Protein VP1 and Inhibits Foot-and-Mouth Disease Virus Replication

BioMed Research International ◽

10.1155/2017/2481348 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8

Author(s):

Huisheng Liu ◽

Qiao Xue ◽

Qiaoying Zeng ◽

Zixiang Zhu ◽

Haixue Zheng

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Host Cells ◽

Cell Protein ◽

Structural Protein ◽

New Information ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD, which affects domestic and wild cloven-hoofed animals. The structural protein VP1 plays an important role in FMDV pathogenesis. However, the interacting partners of VP1 in host cells and the effects of these interactions in FMDV replication remain incompletely elucidated. Here, we identified a porcine cell protein, serine/threonine kinase 3 (STK3), which interacts with FMDV VP1 using the yeast two-hybrid system. The VP1-STK3 interaction was further confirmed by coimmunoprecipitation experiments in human embryonic kidney 293T and porcine kidney 15 (PK-15) cells. The carboxyl-terminal region (amino acids 180–214) of VP1 was essential for its interaction with STK3. The effects of overexpression and underexpressing of STK3 in PK-15 cells were assessed, and the results indicated that STK3 significantly inhibited FMDV replication. Our data expand the role of STK3 during viral infection, provide new information regarding the host cell kinases that are involved in viral replication, and identify potential targets for future antiviral strategies.

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An infectious recombinant foot-and-mouth disease virus expressing a fluorescent marker protein

Journal of General Virology ◽

10.1099/vir.0.052308-0 ◽

2013 ◽

Vol 94 (7) ◽

pp. 1517-1527 ◽

Cited By ~ 20

Author(s):

Julian Seago ◽

Nicholas Juleff ◽

Katy Moffat ◽

Stephen Berryman ◽

John M. Christie ◽

...

Keyword(s):

Disease Virus ◽

Reverse Genetics ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Marker Protein ◽

Fluorescent Marker ◽

Fmdv Infection ◽

Animal Pathogens ◽

Mouth Disease Virus ◽

Foot And Mouth

Foot-and-mouth disease virus (FMDV) is one of the most extensively studied animal pathogens because it remains a major threat to livestock economies worldwide. However, the dynamics of FMDV infection are still poorly understood. The application of reverse genetics provides the opportunity to generate molecular tools to further dissect the FMDV life cycle. Here, we have used reverse genetics to determine the capsid packaging limitations for a selected insertion site in the FMDV genome. We show that exogenous RNA up to a defined length can be stably introduced into the FMDV genome, whereas larger insertions are excised by recombination events. This led us to construct a recombinant FMDV expressing the fluorescent marker protein, termed iLOV. Characterization of infectious iLOV-FMDV showed the virus has a plaque morphology and rate of growth similar to the parental virus. In addition, we show that cells infected with iLOV-FMDV are easily differentiated by flow cytometry using the inherent fluorescence of iLOV and that cells infected with iLOV-FMDV can be monitored in real-time with fluorescence microscopy. iLOV-FMDV therefore offers a unique tool to characterize FMDV infection in vitro, and its applications for in vivo studies are discussed.

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