Hsp90 interacts with multiple dengue virus 2 proteins

Srisutthisamphan, Kanjana; Jirakanwisal, Krit; Ramphan, Suwipa; Tongluan, Natthida; Kuadkitkan, Atichat; Smith, Duncan R.

doi:10.1038/s41598-018-22639-5

Cited by 27 publications

(25 citation statements)

References 36 publications

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“…Heat shock proteins (HSPs) of ~70 kDa and 80 kDa were also identified as cellular receptors for all four DENV serotypes in C6/36 cell line ( 66 , 68 ). HSPs are chaperone proteins involved in the regulation of folding and unfolding of cellular, and upon infection, viral proteins ( 69 ). The 70 kDa protein, also known as heat shock cognate protein (HSC70) or HSPA8, acts as a chaperone protein during DENV entry ( 70 , 71 ).…”

Section: Dengue Virusmentioning

confidence: 99%

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Flavivirus Receptors: Diversity, Identity, and Cell Entry

et al. 2018

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Flaviviruses are emerging and re-emerging arthropod-borne pathogens responsible for significant mortality and morbidity worldwide. The genus comprises more than seventy small, positive-sense, single-stranded RNA viruses, which are responsible for a spectrum of human and animal diseases ranging in symptoms from mild, influenza-like infection to fatal encephalitis and haemorrhagic fever. Despite genomic and structural similarities across the genus, infections by different flaviviruses result in disparate clinical presentations. This review focusses on two haemorrhagic flaviviruses, dengue virus and yellow fever virus, and two neurotropic flaviviruses, Japanese encephalitis virus and Zika virus. We review current knowledge on host-pathogen interactions, virus entry strategies and tropism.

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Section: Dengue Virusmentioning

confidence: 99%

“…HSP90, another heat shock protein, can also act as chaperone. This protein interacts with six DENV proteins ( 69 ). While the involvement of HSP70 and HSP90 in DENV binding to host cells has been reported ( 70 – 72 ), these proteins are not involved in internalization of virus into the host cell ( 73 ).…”

Section: Dengue Virusmentioning

confidence: 99%

Flavivirus Receptors: Diversity, Identity, and Cell Entry

et al. 2018

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“…FKBP52 knockdown decreases NS1 secretion while viral release was not affected. HSP90 has been associated with viral replication of chikungunya virus, Arteriviridae viruses, and hepatitis C virus and has a minor effect on DENV replication (37)(38)(39)(40). However, our results indicate that HSP90 is not associated with NS1 secretion (Fig.…”

Section: Discussionmentioning

confidence: 62%

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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“…FKBP52 knockdown decreases NS1 secretion while viral release was not affected. HSP90 has been associated to viral replication of chikungunya virus, Arteriviridae viruses, Hepatitis C virus and minor effect on DENV replication [36–39], but we could demonstrate the association of this co-chaperone of HSP90 to viral protein trafficking. CyA inhibition by cell treatment with CsA also resulted in diminished NS1 secretion in mosquito cells, without affecting viral release.…”

Section: Discussionmentioning

confidence: 64%

The dengue virus non-structural protein 1 (NS1) is secreted from mosquito cells in association with the intracellular cholesterol transporter chaperone caveolin complex

Ramirez

Ludert

2018

Preprint

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11 12 Keywords: 13 dengue virus; zika virus; yellow fever virus; flavivirus; NS1; caveolin-1; chaperone caveolin 14 complex; viral protein trafficking; unconventional secretion; mosquito cells 15 16 17 ABSTRACT 18 Dengue virus (DENV) is a mosquito-borne virus of the family Flaviviridae. The RNA viral genome 19 encodes for a polyprotein that is co-translationally processed into three structural proteins and . CC-BY 4.0 International license is made available under aThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/370932 doi: bioRxiv preprint 2 20 seven non-structural proteins. The non-structural protein 1 (NS1) is a multifunctional viral protein 21 actively secreted in vertebrate and mosquito cells during DENV infection. In mosquito cells, NS1 22 is secreted in a caveolin-1 (CAV-1) dependent manner by an unconventional pathway. The 23 caveolin chaperone complex (CCC) is a cytoplasmic complex formed by caveolin-1 and the 24 chaperones FKBP52, Cy40 and CyA which is responsible for cholesterol traffic inside the cell. 25 In this work, we demonstrate that in infected mosquito cells, DENV NS1 is secreted by an early 26 and unconventional route that bypasses the Golgi apparatus in close association with the CCC.27 Treatment of mosquito cells with classic secretion inhibitors such as brefeldin A, golgicide A and 28 Fli-06 showed no effect on NS1 secretion, but significant reductions in recombinant luciferase 29 secretion and virion release. Silencing the expression of CAV1, FKBP52 with siRNAs or the 30 inhibition of CyA by cyclosporine A resulted in significant decrease in NS1 secretion without 31 affecting virion release. Using co-localization, co-inmunoprecipitation and proximity ligation 32 assays, NS1 was found to co-localize and interact with all the protein components of the CCC 33 in mosquito infected cells. In addition, CAV-1 and FKBP52 expression was found augmented in 34 DENV infected cells. Finally, the treatment of ZIKV infected mosquito cells with brefeldin A and 35 golgicide A showed no effect on NS1 secretion, while affecting virion release. ZIKV NS1 was 36 also found to co-localize with CAV-1 in infected mosquito cells. These results suggest that in 37 mosquito cells, ZIKV NS1 follows the same secretory pathway observed for DENV NS1. The 38 association of NS1 with the cholesterol transporter CCC agrees with the lipoprotein nature of 39 secreted hexameric NS1. 40 41 AUTHOR SUMMARY . CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/370932 doi: bioRxiv preprint 3 42 Dengue protein NS1 is secreted in infected mosquito and vertebrate cells. In humans, secreted 43 NS1 have been associated with pathogenesis. In mosquito cells, NS1 follows an unconventional 44 secretion pathway that is dependent on Caveolin-1. This work shows that in mosquito cells, NS1 45 secretion is associated to the chaperone caveolin complex, a...

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Hsp90 interacts with multiple dengue virus 2 proteins

Cited by 27 publications

References 36 publications

Flavivirus Receptors: Diversity, Identity, and Cell Entry

Flavivirus Receptors: Diversity, Identity, and Cell Entry

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

The dengue virus non-structural protein 1 (NS1) is secreted from mosquito cells in association with the intracellular cholesterol transporter chaperone caveolin complex

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