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ORIGINAL RESEARCH ARTICLE

TDP43 negatively regulates TBK1-mediated IFN1 production through IRF7 pathway in neurodegenerative diseases

Wenjuan Zhang1 ,  Zhen Yi2 ,  Daihe Yang3 ,  Yifan Hao2 ,  Feng Zhou4 ,  Guohua Song2 ,  Cao Huang5* ,  Yun Zhou6* ,  Bo Huang3,6,7,8,9*
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1 Department of Neurology, Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
2 Department of Nephrology, Shanxi Medical University, Taiyuan, Shanxi, China
3 Department of Anesthesiology, the Affiliated Second People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
4 Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
5 Department of Pathology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania, United States of America
6 Department of Nephrology, First Hospital of Shangxi Medical University, Taiyuan, Shanxi, China
7 Medical Sciences, UCSI University, Kuala Lumpur, Malaysia
8 Department of Nephrology, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, China
9 Laboratory Animal Center, The Fifth Hospital (Shanxi Provincial People’s Hospital) of Shanxi Medical University, Taiyuan, Shanxi, China
Advanced Neurology 2025, 4(1), 94–104; https://doi.org/10.36922/an.6272
Submitted: 19 November 2024 | Revised: 6 January 2025 | Accepted: 15 January 2025 | Published: 7 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Mutations in the genes encoding TAR DNA-binding protein 43 (TDP43) or TANK-binding kinase 1 (TBK1) have been strongly associated with neurological disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP43 is a key component of pathological protein aggregates found in more than 90% of ALS cases, while TBK1 plays a critical role in innate immune signaling and autophagy. Despite these associations, the precise molecular mechanisms linking TDP43 or TBK1 dysfunction to neurodegeneration remain poorly understood. The present study examined the impact of TDP43 on TBK1-mediated type I interferon (IFN1) production in HEK-293T cells. The findings demonstrated that co-expression of TDP43 and TBK1 resulted in a dose-dependent reduction in TBK1 and interferon regulatory factor (IRF) 7 protein levels. In addition, it led to decreased phosphorylation of IRF3 and TBK1. Interestingly, TDP43 knockout cells displayed elevated IRF7 protein levels. Moreover, co-expression of TDP43 and TBK1 significantly suppressed the IFN1 inductions and associated pro-inflammatory cytokines, a suppression reversed by IRF7 overexpression. Further, mechanistic analysis demonstrated that TDP43 facilitates TBK1 degradation through autophagy, resulting in diminished IFN1 induction. These findings uncover a new pathway through which TDP43 disrupts TBK1-mediated signaling through IRF7, potentially contributing to neurodegeneration. Overall, the disrupted TBK1-IRF7-IFN1 axis may therefore represent a critical pathway in TDP43-associated neurodegenerative diseases, offering potential targets for therapeutic intervention.

Graphical abstract
Keywords
Amyotrophic lateral sclerosis
TAR DNA-binding protein 43
TANK-binding kinase 1
Type I interferons
Interferon regulatory factor 7
Funding
This work was supported by the Natural Science Foundation of Shanxi Province (N202304031401121 to B.H., 202403021211044 to B.H., 202302130501011 to Y.Z, 202204051002032 to G.S), the Health Planning Commission foundation of Shanxi Province (N2019017 to B.H., 2024ZYY2A010 to B.H., Renal Disease Clinical and Research Innovation Base Project to Y.Z. and 2021XM to Y.Z.), the Development and Reform Commission Foundation of Shanxi Province (Shanxi Genetic Engineering Center for Experimental Animal Models to Y.Z. and B.H.), and the Shanxi Provincial Medical Administration and Medical Administration Bureau (Role and mechanism of electroacupuncture in the analgesic process of the APP/PS1-MRL/Lpr model to B.H., Y.Z., and J.H., Grant No. 2024ZYY2A010 to B.H., 2022TD2004 to Y.Z.). This work was also financially supported through a demonstration project targeting reform and high-quality development at public hospitals, funded by the Shanxi Provincial Department of Finance supports the (Jin Cai She [2023] No. 23 Project to Y.Z.). This work was also supported by the Shanxi University of Traditional Chinese Medicine (Innovative team cultivation project for the combination of acupuncture and medicine in the prevention and treatment of chronic kidney disease to Y.Z.).
Conflict of interest
The authors declared that they have no competing interests.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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