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Advanced Neurology TDP-43 regulates IFN1 production

of IFN through the activated TLR9 subfamily in plasma resulting in reduced induction of IFN1 through IRF7.
cell-like dendritic cells relies entirely on IRF7, which also In addition, it was found that overexpression of IRF7
orchestrates CD8+ T-cell responses. Whether systemic or alleviates this reduction, restoring IFN1 production. These
localized, IRF7 plays a pivotal role in IFN responses during novel findings uncover an essential role of TDP43 in the
both innate and adaptive immunities. In addition, IRF-7- regulation of TBK1-mediated IFN1 production and offer
17
deficient macrophages exhibit significantly reduced IFN-β new insights into the interplay between TDP43, TBK1,
induction in response to LPS stimulation. These findings IFN pathway, and neurodegenerative diseases.
38
highlight the essential role of IRF-7 in IFN1 production in
response to bacterial components like LPS, underscoring Acknowledgments
the critical importance of IRF7 expression. In this study, None.
co-expression of TDP43 and TBK1 in HEK-293T cells
led to a significant reduction in IRF7 protein levels, while Funding
IRF3 levels remained unaffected. Conversely, CRISPR-
Cas9-generated TDP43 KO cells exhibited increased IRF7 This work was supported by the Natural Science
expression. Moreover, overexpression of IRF7 mitigated Foundation of Shanxi Province (N202304031401121
the inhibitory effects of TDP43, resulting in elevated levels to B.H., 202403021211044 to B.H., 202302130501011
of IFN-α, IFN-β, and ISGs (ISG54 and ISG56). It was to Y.Z, 202204051002032 to G.S), the Health Planning
observed that both IRF7 and the phosphorylation of TBK1 Commission foundation of Shanxi Province (N2019017
and IRF3 were inversely correlated with TDP43 expression to B.H., 2024ZYY2A010 to B.H., Renal Disease Clinical
levels. These findings reveal a novel role for TDP43 in and Research Innovation Base Project to Y.Z. and 2021XM
modulating TBK1-mediated IFN1 production. to Y.Z.), the Development and Reform Commission
Foundation of Shanxi Province (Shanxi Genetic
A prominent pathological hallmark of ALS is the Engineering Center for Experimental Animal Models
mislocalization of proteins and the presence of cytoplasmic to Y.Z. and B.H.), and the Shanxi Provincial Medical
aggregates within motor neurons. Cells rely on both Administration and Medical Administration Bureau (Role
UPS and autophagy-lysosomal pathways for protein and mechanism of electroacupuncture in the analgesic
degradation. Autophagy induction is often assessed process of the APP/PS1-MRL/Lpr model to B.H., Y.Z., and
39
using p62 and LC3-II as markers. Numerous studies have J.H., Grant No. 2024ZYY2A010 to B.H., 2022TD2004 to
highlighted the essential role of TDP43 in regulating Y.Z.). This work was also financially supported through a
autophagy. For example, depletion of TDP43 strongly demonstration project targeting reform and high-quality
promotes transcription factor EB (TFEB) translocation development at public hospitals, funded by the Shanxi
into the nucleus, mediated through its effect on the Provincial Department of Finance supports the (Jin Cai She
mammalian target of rapamycin complex 1 (mTORC1) [2023] No. 23 Project to Y.Z.). This work was also supported
component Raptor, thereby altering the expression of by the Shanxi University of Traditional Chinese Medicine
autophagy-related proteins. In addition, TDP43 depletion
5
disrupts the fusion of autophagosomes and autolysosomes (Innovative team cultivation project for the combination of
by regulating dynactin 1 levels. Furthermore, the absence acupuncture and medicine in the prevention and treatment
8
of TDP43 impairs its ability to bind and stabilize autophagy of chronic kidney disease to Y.Z.).
related 7 (ATG7) mRNA, resulting in compromised Conflict of interest
autophagy and the accumulation of both p62 and LC3-II.
In this study, treatment of HEK-293T cells with autophagy The authors declared that they have no competing interests.
inhibitors MG132+CQ or MG132+A1 led to elevated
expressions of p-TBK1 and p-IRF3, p62, and LC3-II. Author contributions
Furthermore, it was demonstrated that an increased Conceptualization: Cao Huang, Bo Huang
mRNA level of IFNB in HEK-293T cell treated with Data curation: Cao Huang, Bo Huang
MG132+CQ or MG132+A1, but not in the MG132-treated Formal analysis: Cao Huang, Bo Huang
cells. These findings suggest that overexpression of TDP43 Funding acquisition: Guohua Song, Yun Zhou, Bo Huang
may promote TBK1 degradation through the autophagy- Investigation: Zhen Yi, Daihe Yang, Yifan Hao, Feng Zhou,
lysosomal pathway, thereby enhancing IFN-β production. Guohua Song
Methodology: Wenjuan Zhang, Zhen Yi, Daihe Yang, Bo
5. Conclusion Huang

Taken together, this study provides evidence that TDP43 Project administration: Cao Huang, Yun Zhou
negatively regulates TBK1 expression through autophagy, Resources: Cao Huang, Yun Zhou, Bo Huang

Volume 4 Issue 1 (2025) 102 doi: 10.36922/an.6272