Acetylation targets mutant huntingtin to autophagosomes for degradation.
Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA.
Hyunkyung
H
Jeong
Florian
F
Then
Thomas J
TJ
Melia
Joseph R
JR
Mazzulli
Libin
L
Cui
Jeffrey N
JN
Savas
Cindy
C
Voisine
Paolo
P
Paganetti
Naoko
N
Tanese
Anne C
AC
Hart
Ai
A
Yamamoto
Dimitri
D
Krainc
D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins