ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5

Yan Yang; Yuhan Gao; Jingcao Huang; Zhuang Yang; Hongmei Luo; Fangfang Wang; Juan Xu; Yushan Cui; Hong Ding; Zhimei Lin; Xinyu Zhai; Ying Qu; Li Zhang; Ting Liu; Lingqun Ye; Ting Niu; Yuhuan Zheng

doi:10.1172/jci.insight.157081

ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5

Yan Yang, Yuhan Gao, Jingcao Huang, Zhuang Yang, Hongmei Luo, Fangfang Wang, Juan Xu, Yushan Cui, Hong Ding, Zhimei Lin, Xinyu Zhai, Ying Qu, Li Zhang, Ting Liu, Lingqun Ye, Ting Niu, Yuhuan Zheng

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

2 Scopus citations

Abstract

The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2^lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2^hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2^hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.

Original language	English (US)
Article number	e157081
Journal	JCI Insight
Volume	7
Issue number	19
DOIs	https://doi.org/10.1172/jci.insight.157081
State	Published - Oct 10 2022
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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@article{fe0bbbb4b2ef4aba91ea50f706cd10b0,

title = "ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5",

abstract = "The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.",

author = "Yan Yang and Yuhan Gao and Jingcao Huang and Zhuang Yang and Hongmei Luo and Fangfang Wang and Juan Xu and Yushan Cui and Hong Ding and Zhimei Lin and Xinyu Zhai and Ying Qu and Li Zhang and Ting Liu and Lingqun Ye and Ting Niu and Yuhuan Zheng",

note = "Funding Information: We thank the tissue bank of the Department of Hematology, West China Hospital, Sichuan University, for providing samples. This work was supported by grants to YZ from the National Natural Science Foundation of China (No. 82070219 and No. 81870157) and the Sichuan University Faculty Start Fund. We thank Li Fu of the Core Facilities of West China Hospital, Sichuan University, for her kind and professional help with the SPR assays in data acquisition and analysis. We appreciate Qing Yi at Houston Methodist Hospital, for his critical suggestions. Publisher Copyright: Copyright: {\textcopyright} 2022, Yang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2022",

month = oct,

day = "10",

doi = "10.1172/jci.insight.157081",

language = "English (US)",

volume = "7",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "19",

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TY - JOUR

T1 - ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5

AU - Yang, Yan

AU - Gao, Yuhan

AU - Huang, Jingcao

AU - Yang, Zhuang

AU - Luo, Hongmei

AU - Wang, Fangfang

AU - Xu, Juan

AU - Cui, Yushan

AU - Ding, Hong

AU - Lin, Zhimei

AU - Zhai, Xinyu

AU - Qu, Ying

AU - Zhang, Li

AU - Liu, Ting

AU - Ye, Lingqun

AU - Niu, Ting

AU - Zheng, Yuhuan

N1 - Funding Information: We thank the tissue bank of the Department of Hematology, West China Hospital, Sichuan University, for providing samples. This work was supported by grants to YZ from the National Natural Science Foundation of China (No. 82070219 and No. 81870157) and the Sichuan University Faculty Start Fund. We thank Li Fu of the Core Facilities of West China Hospital, Sichuan University, for her kind and professional help with the SPR assays in data acquisition and analysis. We appreciate Qing Yi at Houston Methodist Hospital, for his critical suggestions. Publisher Copyright: Copyright: © 2022, Yang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PY - 2022/10/10

Y1 - 2022/10/10

N2 - The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.

AB - The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.

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DO - 10.1172/jci.insight.157081

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VL - 7

JO - JCI Insight

JF - JCI Insight

IS - 19

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ER -

ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5

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