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| Home > Publications Database > Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. |
| Home > Publications Database > Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. |
| Journal Article | DZNE-2022-00033 |
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2022
Nature Publishing Group UK
[London]
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Please use a persistent id in citations: doi:10.1038/s41467-022-28822-7
Abstract: Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
Keyword(s): Acetylation (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Humans (MeSH) ; Lysine: metabolism (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Protein Processing, Post-Translational (MeSH) ; RNA: metabolism (MeSH) ; Sirtuin 1: genetics (MeSH) ; Sirtuin 1: metabolism (MeSH)
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