TY  - JOUR
AU  - Garcia Morato, Jorge
AU  - Hans, Friederike
AU  - von Zweydorf, Felix
AU  - Feederle, Regina
AU  - Elsässer, Simon J
AU  - Skodras, Angelos
AU  - Gloeckner, Christian Johannes
AU  - Buratti, Emanuele
AU  - Neumann, Manuela
AU  - Kahle, Philipp
TI  - Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.
JO  - Nature Communications
VL  - 13
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2022-00033
SP  - 1223
PY  - 2022
AB  - 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.
KW  - Acetylation
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - DNA-Binding Proteins: metabolism
KW  - Humans
KW  - Lysine: metabolism
KW  - Protein Aggregation, Pathological: metabolism
KW  - Protein Processing, Post-Translational
KW  - RNA: metabolism
KW  - Sirtuin 1: genetics
KW  - Sirtuin 1: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8907366
C6  - pmid:35264561
DO  - DOI:10.1038/s41467-022-28822-7
UR  - https://pub.dzne.de/record/163198
ER  -