PMID- 31028120 OWN - NLM STAT- MEDLINE DCOM- 20200226 LR - 20210731 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 202 IP - 11 DP - 2019 Jun 1 TI - Dlg1 Maintains Dendritic Cell Function by Securing Voltage-Gated K(+) Channel Integrity. PG - 3187-3197 LID - 10.4049/jimmunol.1900089 [doi] AB - Dendritic cells (DCs) play key roles in Ab responses by presenting Ags to lymphocytes and by producing proinflammatory cytokines. In this study, we reported that DC-specific knockout of discs large homologue 1 (Dlg1) resulted in a significantly reduced capacity to mediate Ab responses to both thymus-independent and thymus-dependent Ags in Dlg1 (fl/fl)Cd11c-Cre-GFP mice. Mechanistically, Dlg1-deficient DCs showed severely impaired endocytosis and phagocytosis capacities upon Ag exposure. In parallel, loss of Dlg1 significantly jeopardized the proinflammatory cytokine production by DCs upon TLR stimulation. Thus, Dlg1-deficient DCs lost their functions to support innate and adaptive immunities. At a cellular level, Dlg1 exhibited an indispensable function to maintain membrane potential changes by securing potassium ion (K(+)) efflux and subsequent calcium ion (Ca(2+)) influx events in DCs upon stimulation, both of which are known to be required for proper function of DCs. At a molecular level, Dlg1 did so by retaining the integrity of voltage-gated K(+) channels (including Kv1.3) in DCs. The loss of Dlg1 led to a decreased expression of K(+) channels, resulting in impaired membrane potential changes and, as a consequence, reduced proinflammatory cytokine production, compromised Ag endocytosis, and phagocytosis. In conclusion, this study provided, to our knowledge, a novel insight into Dlg1 and the voltage-gated K(+) channels axis in DC functions. CI - Copyright (c) 2019 by The American Association of Immunologists, Inc. FAU - Dong, Xuejiao AU - Dong X AD - Ministry of Education Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Laboratory for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing 100084, China. FAU - Wei, Lisi AU - Wei L AD - State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China. FAU - Guo, Xueheng AU - Guo X AD - Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China. AD - National Education Examinations Authority, Beijing 100084, China. FAU - Yang, Zhiyong AU - Yang Z AUID- ORCID: 0000-0003-0589-6224 AD - Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143. FAU - Wu, Chuan AU - Wu C AD - Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20851. FAU - Li, Peiyu AU - Li P AUID- ORCID: 0000-0002-1001-7485 AD - Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China. AD - Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People's Hospital, Guangdong Medical University, Shenzhen 518052, China. FAU - Lu, Lu AU - Lu L AD - Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China. FAU - Qi, Hai AU - Qi H AUID- ORCID: 0000-0001-5475-3989 AD - Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China. FAU - Shi, Yan AU - Shi Y AD - Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China. FAU - Hu, Xiaoyu AU - Hu X AD - Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China. FAU - Wu, Li AU - Wu L AD - Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; liulab@tsinghua.edu.cn wuli@tsinghua.edu.cn lychen@pku.edu.cn. FAU - Chen, Liangyi AU - Chen L AD - State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China; liulab@tsinghua.edu.cn wuli@tsinghua.edu.cn lychen@pku.edu.cn. FAU - Liu, Wanli AU - Liu W AUID- ORCID: 0000-0003-0395-2800 AD - Ministry of Education Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Laboratory for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing 100084, China; liulab@tsinghua.edu.cn wuli@tsinghua.edu.cn lychen@pku.edu.cn. LA - eng GR - ZIA BC011755/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190426 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Cytokines) RN - 0 (Discs Large Homolog 1 Protein) RN - 0 (Dlg1 protein, mouse) RN - 0 (Potassium Channels, Voltage-Gated) SB - IM MH - Animals MH - Antibody Formation/genetics MH - Antigen Presentation MH - Calcium Signaling MH - Cells, Cultured MH - Cytokines/metabolism MH - Dendritic Cells/*immunology MH - Discs Large Homolog 1 Protein/genetics/*metabolism MH - Endocytosis/genetics MH - Gene Expression Regulation MH - Membrane Potentials MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Potassium Channels, Voltage-Gated/genetics/*metabolism PMC - PMC8323592 MID - NIHMS1717283 COIS- Disclosures The authors have no financial conflicts of interest. EDAT- 2019/04/28 06:00 MHDA- 2020/02/27 06:00 PMCR- 2021/07/30 CRDT- 2019/04/28 06:00 PHST- 2019/02/04 00:00 [received] PHST- 2019/04/01 00:00 [accepted] PHST- 2019/04/28 06:00 [pubmed] PHST- 2020/02/27 06:00 [medline] PHST- 2019/04/28 06:00 [entrez] PHST- 2021/07/30 00:00 [pmc-release] AID - jimmunol.1900089 [pii] AID - 10.4049/jimmunol.1900089 [doi] PST - ppublish SO - J Immunol. 2019 Jun 1;202(11):3187-3197. doi: 10.4049/jimmunol.1900089. Epub 2019 Apr 26.