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000163198 037__ $$aDZNE-2022-00033
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000163198 1001_ $$0P:(DE-2719)2811855$$aGarcia Morato, Jorge$$b0$$eFirst author$$udzne
000163198 245__ $$aSirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.
000163198 260__ $$a[London]$$bNature Publishing Group UK$$c2022
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000163198 520__ $$aTrans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
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000163198 650_2 $$2MeSH$$aAcetylation
000163198 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000163198 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000163198 650_2 $$2MeSH$$aHumans
000163198 650_2 $$2MeSH$$aLysine: metabolism
000163198 650_2 $$2MeSH$$aProtein Aggregation, Pathological: metabolism
000163198 650_2 $$2MeSH$$aProtein Processing, Post-Translational
000163198 650_2 $$2MeSH$$aRNA: metabolism
000163198 650_2 $$2MeSH$$aSirtuin 1: genetics
000163198 650_2 $$2MeSH$$aSirtuin 1: metabolism
000163198 7001_ $$0P:(DE-2719)2198927$$aHans, Friederike$$b1$$udzne
000163198 7001_ $$0P:(DE-2719)2811552$$avon Zweydorf, Felix$$b2$$udzne
000163198 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b3$$udzne
000163198 7001_ $$00000-0001-8724-4849$$aElsässer, Simon J$$b4
000163198 7001_ $$0P:(DE-2719)2810430$$aSkodras, Angelos$$b5$$udzne
000163198 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b6$$udzne
000163198 7001_ $$aBuratti, Emanuele$$b7
000163198 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b8$$udzne
000163198 7001_ $$0P:(DE-2719)2810803$$aKahle, Philipp$$b9$$eLast author$$udzne
000163198 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-022-28822-7$$gVol. 13, no. 1, p. 1223$$n1$$p1223$$tNature Communications$$v13$$x2041-1723$$y2022
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