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  3. c-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6

c-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6

  • J Biol Chem. 2023 Nov 15:105462. doi: 10.1016/j.jbc.2023.105462.
Yanli Jiang 1,  Longfei Li 1,  Ruozhen Wu 1,  Liulin Wu 1,  Bin Zhang 1,  Jian-Zhi Wang 2,  Rong Liu 1,  Fei Liu 3,  Jing Wang 4,  Xiaochuan Wang 5
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China.
  • 3 Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. Electronic address: fei.liu@opwdd.ny.gov.
  • 4 Department of Immunology School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: wangjhxh@163.com.
  • 5 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen 518000, China. Electronic address: wangxiaochuan@hust.edu.cn.
PMID: 37977223 DOI: 10.1016/j.jbc.2023.105462
Abstract

The accumulation of abnormal Tau Protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role in mediating the activation and polyubiquitination of AEP in response to epidermal growth factor (EGF) stimulation. Additionally, we investigated the involvement of tumor necrosis factor receptor-associated factor 6 (Traf6), an E3 Ligase, in the regulation of AEP levels and its interaction with c-Src. Knockdown of Traf6 effectively inhibited c-Src-induced AEP activation. To gain further insights into the molecular mechanisms, we employed mass spectrometry (MS) to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src. By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. Pharmacological inhibition of c-Src reduced the phosphorylation of Traf6 and inhibited AEP activation in neurons derived from human induced pluripotent stem cells (hiPSCs). Conditional knockout of Traf6 in neurons prevented c-Src-induced AEP activation and subsequent Tau truncation in vivo. Moreover, phosphorylation of Traf6 is highly correlated with AEP activation, Tau368 and pathological Tau (AT8) in Alzheimer's disease (AD) brain. Overall, our study elucidates the role of c-Src in regulating AEP-cleaved Tau through phosphorylating Traf6. Targeting the c-Src/Traf6 pathway may hold potential for the treatment of AD and other tauopathies.

Keywords

AEP; Alzheimer’s disease; Src; Tau pathology; Traf6; truncation.

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