Home > Publications Database > Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. > print

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100 1 _ |a Garcia Morato, Jorge
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245 _ _ |a Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.
260 _ _ |a [London]
|c 2022
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 2 |a Acetylation
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Lysine: metabolism
|2 MeSH
650 _ 2 |a Protein Aggregation, Pathological: metabolism
|2 MeSH
650 _ 2 |a Protein Processing, Post-Translational
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650 _ 2 |a RNA: metabolism
|2 MeSH
650 _ 2 |a Sirtuin 1: genetics
|2 MeSH
650 _ 2 |a Sirtuin 1: metabolism
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700 1 _ |a Hans, Friederike
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700 1 _ |a von Zweydorf, Felix
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700 1 _ |a Feederle, Regina
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700 1 _ |a Elsässer, Simon J
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700 1 _ |a Skodras, Angelos
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700 1 _ |a Gloeckner, Christian Johannes
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700 1 _ |a Buratti, Emanuele
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700 1 _ |a Neumann, Manuela
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700 1 _ |a Kahle, Philipp
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773 _ _ |a 10.1038/s41467-022-28822-7
|g Vol. 13, no. 1, p. 1223
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|t Nature Communications
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