Monitoring of S Protein Maturation in the Endoplasmic Reticulum by Calnexin Is Important for the Infectivity of Severe Acute Respiratory Syndrome Coronavirus

Fukushi, Masaya; Yoshinaka, Yoshiyuki; Matsuoka, Yusuke; Hatakeyama, Seisuke; Ishizaka, Yukihito; Kirikae, Teruo; Sasazuki, Takehiko; Miyoshi‐Akiyama, Tohru

doi:10.1128/jvi.01250-12

Cited by 69 publications

(72 citation statements)

References 49 publications

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“…The folding and maturation of spike protein presumably depends heavily on the ER protein chaperones, such as calreticulin and calnexin. In fact, physical interaction between calnexin and the SARS-CoV spike protein has been determined, and inhibition of calnexin function has been shown to reduce the infectivity of pseudotyped lentivirus bearing the SARS-CoV spike protein (Fukushi et al, 2012). It is therefore not unexpected that studies on coronavirus-induced ER stress have been focused on the spike proteins.…”

Section: Coronavirus Proteins and Er Stressmentioning

confidence: 99%

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

2014

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Coronavirus replication is structurally and functionally associated with the endoplasmic reticulum (ER), a major site of protein synthesis, folding, modification and sorting in the eukaryotic cells. Disturbance of ER homeostasis may occur under various physiological or pathological conditions. In response to the ER stress, signaling pathways of the unfolded protein response (UPR) are activated. UPR is mediated by three ER transmembrane sensors, namely the PKR-like ER protein kinase (PERK), the inositol-requiring protein 1 (IRE1) and the activating transcriptional factor 6 (ATF6). UPR facilitates adaptation to ER stress by reversible translation attenuation, enhancement of ER protein folding capacity and activation of ER-associated degradation (ERAD). In cells under prolonged and irremediable ER stress, UPR can also trigger apoptotic cell death. Accumulating evidence has shown that coronavirus infection causes ER stress and induces UPR in the infected cells. UPR is closely associated with a number of major signaling pathways, including autophagy, apoptosis, the mitogen-activated protein (MAP) kinase pathways, innate immunity and pro-inflammatory response. Therefore, studies on the UPR are pivotal in elucidating the complicated issue of coronavirus-host interaction. In this paper, we present the up-to-date knowledge on coronavirus-induced UPR and discuss its potential involvement in regulation of innate immunity and apoptosis.

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Section: Coronavirus Proteins and Er Stressmentioning

confidence: 99%

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

2014

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“…This usually results in the reduced efficiency of virion assembly and secretion through degradation of viral glycoproteins bearing unprocessed N-linked oligosaccharide. In fact, it was well documented that imino sugars dose-dependently induced the mobility shift as well as degradation of the envelope glycoproteins of viruses from several families (Chang et al, 2009;Fukushi et al, 2012;Qu et al, 2011). Occasionally, the incomplete glucose trimming also affects virion secretion through prevention of the further processing and trafficking of viral glycoproteins.…”

Section: Inhibition Of Er A-glucosidases Compromises the Replication mentioning

confidence: 99%

“…For instance, it has been demonstrated that although the oligosaccharides of VSV G protein or influenza A virus hemagglutinin were greatly altered in the presence of glucosidase inhibitors, their surface expression was not inhibited (Burke et al, 1984). Other studies showed that, while antiviral effect and changes in N-linked glycan structures can become obvious at low concentrations, degradation of viral glycoproteins usually occurs in the cells treated with much higher concentrations of glucosidase inhibitors (Chang et al, 2009;Du et al, 2013;Fukushi et al, 2012;Yu et al, 2012). In addition to suppressing virion assembly and secretion, the antiviral activity of glucosidase inhibitors from these examples might be explained by other mechanisms.…”

Section: Inhibition Of Er A-glucosidases Compromises the Replication mentioning

confidence: 99%

“…In addition, the potent protective effect of a DNJ derivative UV-4 ( Fig. 2) http://www.faqs.org/patents/app/20110065752) and potent antiviral activity and unique antiviral mechanism of other DNJ derivatives against SARS-CoV (Fukushi et al, 2012) also make the imino sugar derivatives potential broad-spectrum antiviral agents against respiratory enveloped RNA virus infections.…”

Section: Antiviral Efficacy and Safety Profiles Of Bu-cast And Nb-dnjmentioning

confidence: 99%

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Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

2013

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Endoplasmic reticulum (ER)-resident α-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER α-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER α-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention.

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“…These experimental discrepancies may be either explained by the different model systems used or by the redundancy of molecular chaperones that can functionally replace calnexin in the ER such as calreticulin (Zhang and Williams, 2006). Co-immunoprecipitation studies have also demonstrated that calnexin can function as chaperone for some viral glycoproteins such as the G protein of vesicular stomatitis virus (VSV) and more recently the S glycoprotein of severe acute respiratory syndrome coronavirus by assisting in their folding and full maturation Fukushi et al, 2012). Calnexin homologues have been identified in many eukaryotes such as plants, yeast, Xenopus (Huang et al, 1993;Yamamoto and Nakamura, 1996) several fish species [Fuller et al, 2004, Danio rerio NM_213448.1, Takifugu rubripes XM_003978229 and XM_003978694] and remarkably in Dictyostelium (Müller-Taubenberger et al, 2001), which implies possible conserved functions for this molecule.…”

Section: Introductionmentioning

confidence: 99%

Rainbow trout (Oncorhynchus mykiss) contain two calnexin genes which encode distinct proteins

Sever

Bols

et al. 2014

Developmental & Comparative Immunology

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Calnexin (IP90/P88) is an integral membrane protein of the endoplasmic reticulum that binds newly synthesized N-linked glycoproteins during their folding in the ER including MHC class I molecule. This manuscript reports the identification of two unique cDNA clones of calnexin in rainbow trout. Both encode putative mature proteins of 579 and 592 aa respectively in addition to a 24 aa signal peptide. Sequence analysis revealed that only one of the two cDNA clones encodes a putative ER retention signal, K/QEDDL, followed by a serine phosphorylation site conserved with mammalian homologs. Amino acid sequence alignment illustrated conservation of the calnexin luminal domain, which consists of a globular and a P domain, in both copies. Southern blotting revealed that there are at least two copies of the calnexin gene in the trout genome and northern blotting showed a wide tissue distribution of an estimated 3 kbp calnexin transcript with an additional minor transcript of 2.3 kbp expressed only in head kidney, spleen PBLs and strongly in RTS11. Importantly, the smaller transcript was predominantly upregulated in RTS11 after a 24h treatment with the calcium ionophore A23187. In western blots, calnexin was detected primarily as a 120 kDa protein and upon A23187 treatment; a 100 kDa band was most prominently expressed. These results suggest that in salmonids there are two differentiated versions of the calnexin gene which encode proteins that may have diverged to perform unique biological functions.

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Monitoring of S Protein Maturation in the Endoplasmic Reticulum by Calnexin Is Important for the Infectivity of Severe Acute Respiratory Syndrome Coronavirus

Cited by 69 publications

References 49 publications

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

Rainbow trout (Oncorhynchus mykiss) contain two calnexin genes which encode distinct proteins

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