The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia’s phagocytic activity under demyelinating conditions.
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4 January 2021
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October 06 2020
Qki is an essential regulator of microglial phagocytosis in demyelination
In Special Collection:
Neurodegenerative Diseases: Biology & Therapeutics
Jiangong Ren,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Congxin Dai,
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
2
Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Xin Zhou,
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
3
Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, Jilin, China
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Joseph A. Barnes,
Joseph A. Barnes
Investigation, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
4
The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX
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Xi Chen,
Xi Chen
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Yunfei Wang,
Yunfei Wang
Formal analysis
5
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Liang Yuan,
Liang Yuan
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
6
Graduate School of Biomedical Sciences, Tufts University, Boston, MA
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Takashi Shingu,
Takashi Shingu
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Amy B. Heimberger,
Amy B. Heimberger
Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing - original draft
7
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX
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Yiwen Chen,
Yiwen Chen
Formal analysis
8
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Jian Hu
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
4
The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX
Correspondence to Jian Hu: jhu3@mdanderson.org
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Jiangong Ren
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Congxin Dai
Investigation, Methodology, Resources, Software
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
2
Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Xin Zhou
Formal analysis, Investigation, Resources, Visualization, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
3
Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, Jilin, China
Joseph A. Barnes
Investigation, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
4
The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX
Xi Chen
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Yunfei Wang
Formal analysis
5
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Liang Yuan
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
6
Graduate School of Biomedical Sciences, Tufts University, Boston, MA
Takashi Shingu
Investigation
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Amy B. Heimberger
Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing - original draft
7
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX
Yiwen Chen
Formal analysis
8
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Jian Hu
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
4
The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX
*
J. Ren, C. Dai, and X. Zhou contributed equally to this paper.
Correspondence to Jian Hu: jhu3@mdanderson.org
Received:
February 22 2019
Revision Received:
August 07 2019
Accepted:
September 03 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
American Cancer Society
(RSG-17-029-01-CSM)
Cancer Prevention and Research Institute of Texas
(RP120348, RP170002)
National Cancer Institute
(P30CA016672)
National Institutes of Health
(R01 HL11879)
National Multiple Sclerosis Society
(NO AWARD)
Sontag Foundation
(NO AWARD)
University of Texas MD Anderson Cancer Center
(NO AWARD)
© 2020 Ren et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (1): e20190348.
Article history
Received:
February 22 2019
Revision Received:
August 07 2019
Accepted:
September 03 2020
Citation
Jiangong Ren, Congxin Dai, Xin Zhou, Joseph A. Barnes, Xi Chen, Yunfei Wang, Liang Yuan, Takashi Shingu, Amy B. Heimberger, Yiwen Chen, Jian Hu; Qki is an essential regulator of microglial phagocytosis in demyelination. J Exp Med 4 January 2021; 218 (1): e20190348. doi: https://doi.org/10.1084/jem.20190348
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