期刊
EMBO JOURNAL
卷 39, 期 15, 页码 -出版社
WILEY
DOI: 10.15252/embj.2019103457
关键词
BACE1; GluK2; 3; HNK-1; protein trafficking; SEZ6
资金
- Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy within Munich Cluster for Systems Neurology [EXC 2145, 390857198]
- Centers of Excellence in Neurodegeneration [FOR2290]
- BMBF
- JPND project PMG-AD
- Bayerisches Hochschulzentrum fur Mittel-, Ost- und Sudosteuropa (BAYHOST)
- UK Dementia Research Institute - DRI Ltd - Medical Research Council
- Alzheimer's Society
- Alzheimer Research UK [UKDRI-1010]
- UKRI Future Leaders Fellowship [MR/S017003/1]
- BrightFocus Foundation [A2019112S]
- National Institute of General Medical Sciences of the United States National Institutes of Health [GM134083-01]
- Australian National Health and Medical Research Council [GNT10008046, GNT1058672, GNT1140050]
- Parkinson Fonds Deutschland
- Hilde Ulrichs Stiftung
- Friede Springer Stiftung
- Deutsche Stiftung fur Neurologie
- Luneburg Heritage
- MRC [UKDRI-1010] Funding Source: UKRI
- UKRI [MR/S017003/1] Funding Source: UKRI
Seizure protein 6 (SEZ6) is required for the development and maintenance of the nervous system, is a major substrate of the protease BACE1 and is linked to Alzheimer's disease (AD) and psychiatric disorders, but its molecular functions are not well understood. Here, we demonstrate that SEZ6 controls glycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits. Loss of SEZ6 reduced surface levels of GluK2/3 in primary neurons and reduced kainate-evoked currents in CA1 pyramidal neurons in acute hippocampal slices. Mechanistically, loss of SEZ6in vitroandin vivoprevented modification of GluK2/3 with the human natural killer-1 (HNK-1) glycan, a modulator of GluK2/3 function. SEZ6 interacted with GluK2 through its ectodomain and promoted post-endoplasmic reticulum transport of GluK2 in the secretory pathway in heterologous cells and primary neurons. Taken together, SEZ6 acts as a new trafficking factor for GluK2/3. This novel function may help to better understand the role of SEZ6 in neurologic and psychiatric diseases.
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