Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies

Abstract

Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.

Keywords: RNA metabolism; RNA-binding proteins; TDP-43; neuronal dysfunctions; viral entry; viral latency; viral replication.

Figure 1

Relationship between TDP-43-controlled immune mediators and neuronal dysfunctions/viral infection. Regulation of TDP-43 levels contributes to increase or reduce the expression of different immune mediators, such as IL-1β, NF-κB, IL-6, ICAM-1, and TNF-α. Up- and downregulated effects are indicated with upward and downward arrows, respectively. Neurodegenerative and viral implications are also reported in the table.

Figure 2

Overview of several viruses linked to TDP-43 proteinopathy. TDP-43 is involved in several infections by DNA and RNA viruses, including Coxsackievirus B3 (CVB3), Theiler’s murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). This picture was created with Biorender.com. Predicted TDP-43 ternary-structure was created using AlphaFold algorithm and reprinted with the permission from Refs. [153,154].