Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

Dawar, Farman Ullah; Tu, Jiagang; Khattak, Muhammad Nasir Khan; Mei, Jie; Lin, Li

doi:10.21775/cimb.021.001

Cited by 45 publications

(42 citation statements)

References 86 publications

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“…Our study suggests a potential link between virus dependence on CypA/B and viral susceptibility to MxB inhibition. For example, not only are HIV-1 and HCV sensitive to CsA inhibition (25), but JEV and DENV were also reported to be inhibited by CsA (30,31). In contrast to these four viruses that are subjected to MxB restriction, ZIKV resists MxB as well as CsA inhibition (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human MxB Inhibits the Replication of Hepatitis C Virus

Liu

et al. 2019

J Virol

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Type I interferon (IFN) inhibits viruses by inducing the expression of antiviral proteins. The IFN-induced myxovirus resistance B (MxB) protein has been reported to inhibit a limited number of viruses, including HIV-1 and herpesviruses, but its antiviral coverage remains to be explored further. Here we show that MxB interferes with RNA replication of hepatitis C virus (HCV) and significantly inhibits viral replication in a cyclophilin A (CypA)-dependent manner. Our data further show that MxB interacts with the HCV protein NS5A, thereby impairing NS5A interaction with CypA and NS5A localization to the endoplasmic reticulum, two events essential for HCV RNA replication. Interestingly, we found that MxB significantly inhibits two additional CypA-dependent viruses of the Flaviviridae family, namely, Japanese encephalitis virus and dengue virus, suggesting a potential link between virus dependence on CypA and virus susceptibility to MxB inhibition. Collectively, these data have identified MxB as a key factor behind IFN-mediated suppression of HCV infection, and they suggest that other CypA-dependent viruses may also be subjected to MxB restriction. IMPORTANCE Viruses of the Flaviviridae family cause major illness and death around the world and thus pose a great threat to human health. Here we show that IFN-inducible MxB restricts several members of the Flaviviridae, including HCV, Japanese encephalitis virus, and dengue virus. This finding not only suggests an active role of MxB in combating these major pathogenic human viruses but also significantly expands the antiviral spectrum of MxB. Our study further strengthens the link between virus dependence on CypA and susceptibility to MxB restriction and also suggests that MxB may employ a common mechanism to inhibit different viruses. Elucidating the antiviral functions of MxB advances our understanding of IFN-mediated host antiviral defense and may open new avenues to the development of novel antiviral therapeutics.

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Section: Discussionmentioning

confidence: 99%

Human MxB Inhibits the Replication of Hepatitis C Virus

Liu

et al. 2019

J Virol

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“…Luo et al 73 had speculated that nucleocapsid protein (NP) of SARS-CoV played an important role in the process of virus particle assembly and release and it might also bind to human cyclophilin A. Cyclophilin A is a key member of immunophilins acting as a cellular receptor for cyclosporine A. 74 Cyclophilin A has played an important role in viral infection which either facilitates or inhibits their replication. 74 In addition, the inhibition of cyclophilins by cyclosporine A could block the replication of coronavirus of all genera, including SARS-CoV as well as avian infectious bronchitis virus.…”

Section: Cyclosporine Amentioning

confidence: 99%

“…74 Cyclophilin A has played an important role in viral infection which either facilitates or inhibits their replication. 74 In addition, the inhibition of cyclophilins by cyclosporine A could block the replication of coronavirus of all genera, including SARS-CoV as well as avian infectious bronchitis virus. 75 Therefore, the nonimmunosuppressive derivatives of cyclosporine A might serve as broad-range coronavirus inhibitors applicable against the emerging novel virus-like COVID-19.…”

Section: Cyclosporine Amentioning

confidence: 99%

Potential interventions for novel coronavirus in China: A systematic review

Zhang

Liu

2020

Journal of Medical Virology

1,148

1,178

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An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA-virus infection and we have found that general treatments, coronavirus-specific treatments, and antiviral treatments should be useful in fighting COVID-19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA-virus vaccines including influenza vaccine should be immunized for uninfected people and health care

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“…CyA inhibition by cell treatment with CsA also resulted in diminished NS1 secretion in mosquito cells without affecting viral release. However, CyA has been associated with viral packing and viral release in other viruses, such as coronaviruses, hepatitis C virus, HIV, and others (41)(42)(43). Finally, Cy40 knockdown had no effect on either NS1 secretion or viral release.…”

Section: Discussionmentioning

confidence: 95%

The Dengue Virus Nonstructural Protein 1 (NS1) Is Secreted from Mosquito Cells in Association with the Intracellular Cholesterol Transporter Chaperone Caveolin Complex

Rosales

Ludert

2019

J Virol

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Dengue virus (DENV) is a mosquito-borne virus of the family Flaviviridae. The RNA viral genome encodes three structural and seven nonstructural proteins. Nonstructural protein 1 (NS1) is a multifunctional protein actively secreted in vertebrate and mosquito cells during infection. In mosquito cells, NS1 is secreted in a caveolin-1-dependent manner by an unconventional route. The caveolin chaperone complex (CCC) is a cytoplasmic complex formed by caveolin-1 and the chaperones FKBP52, Cy40, and CyA and is responsible for the cholesterol traffic inside the cell. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 associates with and relies on the CCC for secretion. Treatment of mosquito cells with classic secretion inhibitors, such as brefeldin A, Golgicide A, and Fli-06, showed no effect on NS1 secretion but significant reductions in recombinant luciferase secretion and virion release. Silencing the expression of CAV-1 or FKBP52 with short interfering RNAs or the inhibition of CyA by cyclosporine resulted in significant decrease in NS1 secretion, again without affecting virion release. Colocalization, coimmunoprecipitation, and proximity ligation assays indicated that NS1 colocalizes and interacts with all proteins of the CCC. In addition, CAV-1 and FKBP52 expression was found augmented in DENV-infected cells. Results obtained with Zika virus-infected cells suggest that in mosquito cells, ZIKV NS1 follows the same secretory pathway as that observed for DENV NS1. These results uncover important differences in the dengue virus-cell interactions between the vertebrate host and the mosquito vector as well as novel functions for the chaperone caveolin complex. IMPORTANCE The dengue virus protein NS1 is secreted efficiently from both infected vertebrate and mosquito cells. Previously, our group reported that NS1 secretion in mosquito cells follows an unconventional secretion pathway dependent on caveolin-1. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 secretion takes place in association with the chaperone caveolin complex, a complex formed by caveolin-1 and the chaperones FKBP52, CyA, and Cy40, which are in charge of cholesterol transport inside the cell. Results obtained with ZIKV-infected mosquito cells suggest that ZIKV NS1 is released following an unconventional secretory route in association with the chaperone caveolin complex. These results uncover important differences in the virus-cell interactions between the vertebrate host and the mosquito vector, as well as novel functions for the chaperone caveolin complex. Moreover, manipulation of the NS1 secretory route may prove a valuable strategy to combat these two mosquito-borne diseases. Volume 93 Issue 4 e01985-18 jvi.asm.org 2 on March 18, 2020 by guest http://jvi.asm.org/ Downloaded from plasma membrane, mediated by the CCC, to reach the extracellular space. In addition, data are presented suggesting that a similar pathway is used for the secretion of Zika virus NS1 protein in infected m...

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Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

Cited by 45 publications

References 86 publications

Human MxB Inhibits the Replication of Hepatitis C Virus

Human MxB Inhibits the Replication of Hepatitis C Virus

Potential interventions for novel coronavirus in China: A systematic review

The Dengue Virus Nonstructural Protein 1 (NS1) Is Secreted from Mosquito Cells in Association with the Intracellular Cholesterol Transporter Chaperone Caveolin Complex

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