Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders

B. Dai; A. Y. Chen; C. P. Corkum; R. J. Peroutka; A. Landon; S. Houng; P. A. Muniandy; Y. Zhang; E. Lehrmann; K. Mazan-Mamczarz; J. Steinhardt; M. Shlyak; Q. C. Chen; K. G. Becker; F. Livak; T. I. Michalak; R. Talwani; R. B. Gartenhaus

doi:10.1038/onc.2015.364

Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders

B. Dai, A. Y. Chen, C. P. Corkum, R. J. Peroutka, A. Landon, S. Houng, P. A. Muniandy, Y. Zhang, E. Lehrmann, K. Mazan-Mamczarz, J. Steinhardt, M. Shlyak, Q. C. Chen, K. G. Becker, F. Livak, T. I. Michalak, R. Talwani, R. B. Gartenhaus^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.

Original language	English (US)
Pages (from-to)	2979-2990
Number of pages	12
Journal	Oncogene
Volume	35
Issue number	23
DOIs	https://doi.org/10.1038/onc.2015.364
State	Published - Jun 9 2016

Funding

This work was supported in part by a Merit Review Award from the Department of Veterans Affairs (RBG), R01AA017972 (RBG) and R01CA164311 (RBG) from the National Institutes of Health, as well as MOP-126056 (TIM) from the Canadian Institutes of Health Research and the Canada Research Chair Program in Viral Hepatitis/Immunology (TIM). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging (YZ, EL and KGB).

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dai, B., Chen, A. Y., Corkum, C. P., Peroutka, R. J., Landon, A., Houng, S., Muniandy, P. A., Zhang, Y., Lehrmann, E., Mazan-Mamczarz, K., Steinhardt, J., Shlyak, M., Chen, Q. C., Becker, K. G., Livak, F., Michalak, T. I., Talwani, R., & Gartenhaus, R. B. (2016). Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders. Oncogene, 35(23), 2979-2990. https://doi.org/10.1038/onc.2015.364

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title = "Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders",

abstract = "B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.",

author = "B. Dai and Chen, {A. Y.} and Corkum, {C. P.} and Peroutka, {R. J.} and A. Landon and S. Houng and Muniandy, {P. A.} and Y. Zhang and E. Lehrmann and K. Mazan-Mamczarz and J. Steinhardt and M. Shlyak and Chen, {Q. C.} and Becker, {K. G.} and F. Livak and Michalak, {T. I.} and R. Talwani and Gartenhaus, {R. B.}",

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doi = "10.1038/onc.2015.364",

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Dai, B, Chen, AY, Corkum, CP, Peroutka, RJ, Landon, A, Houng, S, Muniandy, PA, Zhang, Y, Lehrmann, E, Mazan-Mamczarz, K, Steinhardt, J, Shlyak, M, Chen, QC, Becker, KG, Livak, F, Michalak, TI, Talwani, R & Gartenhaus, RB 2016, 'Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders', Oncogene, vol. 35, no. 23, pp. 2979-2990. https://doi.org/10.1038/onc.2015.364

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AU - Chen, A. Y.

AU - Corkum, C. P.

AU - Peroutka, R. J.

AU - Landon, A.

AU - Houng, S.

AU - Muniandy, P. A.

AU - Zhang, Y.

AU - Lehrmann, E.

AU - Mazan-Mamczarz, K.

AU - Steinhardt, J.

AU - Shlyak, M.

AU - Chen, Q. C.

AU - Becker, K. G.

AU - Livak, F.

AU - Michalak, T. I.

AU - Talwani, R.

AU - Gartenhaus, R. B.

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N2 - B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.

AB - B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.

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Hepatitis C virus upregulates B-cell receptor signaling: A novel mechanism for HCV-associated B-cell lymphoproliferative disorders

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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