%0 Journal Article
%A Garcia Morato, Jorge
%A Hans, Friederike
%A von Zweydorf, Felix
%A Feederle, Regina
%A Elsässer, Simon J
%A Skodras, Angelos
%A Gloeckner, Christian Johannes
%A Buratti, Emanuele
%A Neumann, Manuela
%A Kahle, Philipp
%T Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.
%J Nature Communications
%V 13
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DZNE-2022-00033
%P 1223
%D 2022
%X 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.
%K Acetylation
%K Amyotrophic Lateral Sclerosis: metabolism
%K DNA-Binding Proteins: metabolism
%K Humans
%K Lysine: metabolism
%K Protein Aggregation, Pathological: metabolism
%K Protein Processing, Post-Translational
%K RNA: metabolism
%K Sirtuin 1: genetics
%K Sirtuin 1: metabolism
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC8907366
%$ pmid:35264561
%R 10.1038/s41467-022-28822-7
%U https://pub.dzne.de/record/163198