Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export

Duan, Lauren; Zaepfel, Benjamin L.; Aksenova, Vasilisa; Dasso, Mary; Rothstein, Jeffrey D.; Kaláb, Petr; Hayes, Lindsey R.

doi:10.1016/j.celrep.2022.111106

Cited by 43 publications

(73 citation statements)

References 140 publications

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“…We decided to focus on TDP-43, or TAR DNA-binding protein-43, which was initially identified as a repressor of HIV-1 transcription (56) and then found to be involved in the life cycle of several DNA and positive-stranded RNA viruses (57). It is a ubiquitous, 414 amino acids long RNA/DNA binding protein with a predominantly nuclear localization (58). Beyond its role as a transcription factor, TDP-43 regulates multiple aspects of mRNA metabolism, including splicing, nucleo-cytoplasmic transport, stability and translation (59).…”

Section: Resultsmentioning

confidence: 99%

The RBPome of influenza A virus mRNA reveals a role for TDP-43 in viral replication

Dupont

Krischuns

Gianetto

et al. 2023

Preprint

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Recent technical advances have significantly improved our understanding of the RNA-binding protein (RBP) repertoire present within eukaryotic cells, with a particular focus on the RBPs that interact with cellular polyadenylated mRNAs. However, recent studies utilising the same technologies have begun to tease apart the RBP interactome of viral mRNAs, notably SARS-CoV-2, revealing both similarities and differences between the RBP profiles of viral and cellular mRNAs. Herein, we comprehensively identified the RBPs that associate with the NP mRNA of an influenza A virus. Moreover, we provide evidence that the viral polymerase is essential for the recruitment of RPBs to viral mRNAs through direct polymerase-RBP interactions during transcription. We show that loss of TDP-43, which associates with the viral mRNAs, results in lower levels of viral mRNAs within infected cells, and a decreased yield of infectious viral particles. Overall, our results uncover an important role for TDP-43 in the influenza A virus replication cycle via a direct interaction with viral mRNAs, and point to a role of the viral polymerase in orchestrating the assembly of viral mRNPs.

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Section: Resultsmentioning

confidence: 99%

The RBPome of influenza A virus mRNA reveals a role for TDP-43 in viral replication

Dupont

Krischuns

Gianetto

et al. 2023

Preprint

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“…RNA-binding de cient TDP-43, including variants with RRM mutations or deletions, showed increased TDP-43 phase separation, aggregation, nuclear egress, and neurotoxicity 34,58,63,66 . Conversely, enhancing RNA binding mitigates these phenotypes 67,119,120 , likely in large part due to TDP-43 retention within the nucleus 36 . We hypothesize that the reduced nucleic-acid binding capacity of acetylation-mimic TDP-43 K145Q is responsible for the TDP-43 mislocalization, aggregation, and RNA dyshomeostasis observed in our model, and the neurotoxicity and de cits these impart.…”

Section: Discussionmentioning

confidence: 99%

“…Disease-linked transcriptomic and splicing defects are prevalent in acetylation-mimic TDP-43 KQ/KQ mice TDP-43 acetylation drives RNA dissociation and loss of TDP-43 function 52 , implying that reduced RNAbinding capacity may impact transcriptional regulation and mRNA splicing 36,50,91 . We performed total RNA sequencing on neocortex and hippocampus tissue from 18-month-old TDP-43 wt or TDP-43 KQ/KQ mice to determine how TDP-43 acetylation affects RNA pro les in vivo.…”

Section: Tdp-43 Acetylation-mimic Mice Develop Age-dependent Cognitiv...mentioning

confidence: 99%

“…Structurally, nuclear retention is primarily mediated by an N-terminal nuclear localization sequence (NLS) through interactions with α1/βimportins 32,33 , and association with nucleic acids is mediated by two tandem RNA recognition motifs (RRM1/RRM2) 34,35 (Fig. S1A), however there is interplay between nucleic acid binding and nuclear localization 36,37 . The C-terminal glycine-rich domain (also termed the intrinsically disordered or low…”

Section: Introductionmentioning

confidence: 99%

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RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

Necarsulmer

Simon

Evangelista

et al. 2023

Preprint

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TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss-of-TDP-43-function in primary mouse and human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

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“…The LLPS is driven by just a few aromatic residues, a feature that has been attributed to the presence of the α-helix stimulating inter-molecular contacts [ 68 ]. In healthy cells, TDP-43 proteins normally egress nuclei by passive diffusion, independent of facilitated mRNA export, and their nuclear localization relies on binding to GU-rich nuclear RNAs [ 69 ]. Table 1 highlighted some RBPs connected to neurodegenerative disease and the effect of their inhibitors.…”

Section: Rbps Assume Diverse Types Of Functions In Mammalian Cellsmentioning

confidence: 99%

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

2022

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RNA-binding proteins (RBPs) have emerged as important players in multiple biological processes including transcription regulation, splicing, R-loop homeostasis, DNA rearrangement, miRNA function, biogenesis, and ribosome biogenesis. A large number of RBPs had already been identified by different approaches in various organisms and exhibited regulatory functions on RNAs’ fate. RBPs can either directly or indirectly interact with their target RNAs or mRNAs to assume a key biological function whose outcome may trigger disease or normal biological events. They also exert distinct functions related to their canonical and non-canonical forms. This review summarizes the current understanding of a wide range of RBPs’ functions and highlights their emerging roles in the regulation of diverse pathways, different physiological processes, and their molecular links with diseases. Various types of diseases, encompassing colorectal carcinoma, non-small cell lung carcinoma, amyotrophic lateral sclerosis, and Severe acute respiratory syndrome coronavirus 2, aberrantly express RBPs. We also highlight some recent advances in the field that could prompt the development of RBPs-based therapeutic interventions.

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Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export

Cited by 43 publications

References 140 publications

The RBPome of influenza A virus mRNA reveals a role for TDP-43 in viral replication

The RBPome of influenza A virus mRNA reveals a role for TDP-43 in viral replication

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy

Roles of RNA-binding proteins in neurological disorders, COVID-19, and cancer

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