title: The endoplasmic reticulum adaptor protein ERAdP initiates NK cell activation via the Ubc13-mediated NF-κB pathway.
abstract: NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-κB pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-κB essential modulator ubiquitination to trigger the Ubc13-mediated NF-κB pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Lu
authors.initials: L
authors.lastname: Hao
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Buqing
authors.initials: B
authors.lastname: Ye
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;
authors.forename: Bo
authors.initials: B
authors.lastname: Long
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Pingping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Benyu
authors.initials: B
authors.lastname: Liu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Liuliu
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing100101, China; and fanz@moon.ibp.ac.cn ytian@ibp.ac.cn peifli@ioz.ac.cn.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
authors.affiliation: Beijing Noncoding RNA Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China fanz@moon.ibp.ac.cn ytian@ibp.ac.cn peifli@ioz.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; fanz@moon.ibp.ac.cn ytian@ibp.ac.cn peifli@ioz.ac.cn.
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000596790:ERAdP protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D007371:Interferon-gamma; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; D051550:I-kappa B Kinase