Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Keo Heun Lim; Eun Sook Park; Doo Hyun Kim; Kyung Cho Cho; Kwang Pyo Kim; Yong Kwang Park; Sung Hyun Ahn; Seung Hwa Park; Kee Hwan Kim; Chang Wook Kim; Hong Seok Kang; Ah Ram Lee; Soree Park; Heewoo Sim; Juhee Won; Kieun Seok; Jueng Soo You; Jeong Hoon Lee; Nam Joon Yi; Kwang Woong Lee; Kyung Suk Suh; Baik L. Seong; Kyun Hwan Kim

doi:10.1136/gutjnl-2016-312742

Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Keo Heun Lim, Eun Sook Park, Doo Hyun Kim, Kyung Cho Cho, Kwang Pyo Kim, Yong Kwang Park, Sung Hyun Ahn, Seung Hwa Park, Kee Hwan Kim, Chang Wook Kim, Hong Seok Kang, Ah Ram Lee, Soree Park, Heewoo Sim, Juhee Won, Kieun Seok, Jueng Soo You, Jeong Hoon Lee, Nam Joon Yi, Kwang Woong LeeKyung Suk Suh, Baik L. Seong, Kyun Hwan Kim

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

43 Citations (Scopus)

Abstract

Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. Conclusions We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.

Original language	English
Pages (from-to)	166-178
Number of pages	13
Journal	Gut
Volume	67
Issue number	1
DOIs	https://doi.org/10.1136/gutjnl-2016-312742
Publication status	Published - 2018 Jan 1

Bibliographical note

Funding Information:
Funding This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014).

Funding Information:
This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014).

Publisher Copyright:
© Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

All Science Journal Classification (ASJC) codes

Gastroenterology

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10.1136/gutjnl-2016-312742

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Lim, K. H., Park, E. S., Kim, D. H., Cho, K. C., Kim, K. P., Park, Y. K., Ahn, S. H., Park, S. H., Kim, K. H., Kim, C. W., Kang, H. S., Lee, A. R., Park, S., Sim, H., Won, J., Seok, K., You, J. S., Lee, J. H., Yi, N. J., ... Kim, K. H. (2018). Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22. Gut, 67(1), 166-178. https://doi.org/10.1136/gutjnl-2016-312742

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title = "Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22",

abstract = "Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. Conclusions We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.",

author = "Lim, {Keo Heun} and Park, {Eun Sook} and Kim, {Doo Hyun} and Cho, {Kyung Cho} and Kim, {Kwang Pyo} and Park, {Yong Kwang} and Ahn, {Sung Hyun} and Park, {Seung Hwa} and Kim, {Kee Hwan} and Kim, {Chang Wook} and Kang, {Hong Seok} and Lee, {Ah Ram} and Soree Park and Heewoo Sim and Juhee Won and Kieun Seok and You, {Jueng Soo} and Lee, {Jeong Hoon} and Yi, {Nam Joon} and Lee, {Kwang Woong} and Suh, {Kyung Suk} and Seong, {Baik L.} and Kim, {Kyun Hwan}",

note = "Funding Information: Funding This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014). Funding Information: This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014). Publisher Copyright: {\textcopyright} Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.",

year = "2018",

month = jan,

day = "1",

doi = "10.1136/gutjnl-2016-312742",

language = "English",

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pages = "166--178",

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Lim, KH, Park, ES, Kim, DH, Cho, KC, Kim, KP, Park, YK, Ahn, SH, Park, SH, Kim, KH, Kim, CW, Kang, HS, Lee, AR, Park, S, Sim, H, Won, J, Seok, K, You, JS, Lee, JH, Yi, NJ, Lee, KW, Suh, KS, Seong, BL & Kim, KH 2018, 'Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22', Gut, vol. 67, no. 1, pp. 166-178. https://doi.org/10.1136/gutjnl-2016-312742

TY - JOUR

T1 - Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

AU - Lim, Keo Heun

AU - Park, Eun Sook

AU - Kim, Doo Hyun

AU - Cho, Kyung Cho

AU - Kim, Kwang Pyo

AU - Park, Yong Kwang

AU - Ahn, Sung Hyun

AU - Park, Seung Hwa

AU - Kim, Kee Hwan

AU - Kim, Chang Wook

AU - Kang, Hong Seok

AU - Lee, Ah Ram

AU - Park, Soree

AU - Sim, Heewoo

AU - Won, Juhee

AU - Seok, Kieun

AU - You, Jueng Soo

AU - Lee, Jeong Hoon

AU - Yi, Nam Joon

AU - Lee, Kwang Woong

AU - Suh, Kyung Suk

AU - Seong, Baik L.

AU - Kim, Kyun Hwan

N1 - Funding Information: Funding This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014). Funding Information: This study was supported by the National Research Foundation (NRF) grant funded by the Korean government (No. 2013R1A2A2A01068194, No. 2014M3A9A8064633, NRF-2016R1A5A2012284 and 2016R1A2B4007531). This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute , funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C-1529-020014). Publisher Copyright: © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. Conclusions We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.

AB - Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. Conclusions We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system.

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Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Abstract

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