TAR DNA-binding protein 43 – stress granule protein–protein interaction interface (TDP-43–SG PPI interface)

TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA-binding protein that plays a vital role in RNA splicing, transport, and stability (UniProt Q13148). Under conditions of cellular stress, TDP-43 translocates from the nucleus to the cytoplasm, where it is recruited into stress granules (SGs)—membraneless organelles formed through liquid-liquid phase separation (PubMed: 32814902). The interaction between TDP-43 and SG-resident proteins, such as G3BP1 and TIA1, is a critical step in the cellular stress response; however, chronic stress or disease-associated mutations can cause these dynamic SGs to mature into irreversible, toxic protein aggregates (PubMed: 30104397). These aggregates are the pathological hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The TDP-43–stress granule protein–protein interaction interface has emerged as a therapeutic target, with the goal of preventing the sequestration of TDP-43 into granules and its subsequent conversion into insoluble inclusions. Experimental strategies include the use of small molecules like ISRIB to modulate the integrated stress response or specific PPI inhibitors designed to disrupt the recruitment of TDP-43 to the SG scaffold. Successfully targeting this interface could preserve nuclear TDP-43 function and reduce the proteotoxic burden in affected neurons.

Other names

TDP-43 stress granule recruitment interfaceTDP-43-G3BP1 interactionTDP-43-TIA1 interactionTARDBP-stress granule interfaceTDP-43-SG PPI

Inhibition of the recruitment of TDP-43 into cytoplasmic stress granules by disrupting its interaction with scaffold proteins like G3BP1 or TIA1, thereby preventing the liquid-to-solid phase transition into pathological aggregates (PubMed: 32814902).