Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43.

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.

• Authors: Jorge Garcia Morato, Friederike Hans, Felix von Zweydorf, Regina Feederle, Simon J Elsässer, Angelos A Skodras, Christian Johannes Gloeckner, Emanuele Buratti, Manuela Neumann, Philipp J Kahle
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 1223 (03 09 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35264561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human
• RNA
• SIRT1 protein, human
• Sirtuin 1
• Lysine

Topics

• Acetylation
• Amyotrophic Lateral Sclerosis (metabolism)
• DNA-Binding Proteins (metabolism)
• Humans
• Lysine (metabolism)
• Protein Aggregation, Pathological (metabolism)
• Protein Processing, Post-Translational
• RNA (metabolism)
• Sirtuin 1 (genetics, metabolism)