title: Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin.
abstract: Autophagy controls and executes the turnover of abnormally aggregated proteins. MAP1S interacts with the autophagy marker LC3 and positively regulates autophagy flux. HDAC4 associates with the aggregation-prone mutant huntingtin protein (mHTT) that causes Huntington's disease, and colocalizes with it in cytosolic inclusions. It was suggested HDAC4 interacts with MAP1S in a yeast two-hybrid screening. Here, we found that MAP1S interacts with HDAC4 via a HDAC4-binding domain (HBD). HDAC4 destabilizes MAP1S, suppresses autophagy flux and promotes the accumulation of mHTT aggregates. This occurs by an increase in the deacetylation of the acetylated MAP1S. Either suppression of HDAC4 with siRNA or overexpression of the MAP1S HBD leads to stabilization of MAP1S, activation of autophagy flux and clearance of mHTT aggregates. Therefore, specific interruption of the HDAC4-MAP1S interaction with short peptides or small molecules to enhance autophagy flux may relieve the toxicity of mHTT associated with Huntington's disease and improve symptoms of HD patients.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yue
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.|Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Guibin
authors.initials: G
authors.lastname: Xu
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.|Department of Urology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health, Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health, Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Exiris Srl, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Wallace L
authors.initials: WL
authors.lastname: McKeehan
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.|Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, TX 77843, USA.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D001343:Autophagy; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; C493240:MAP1S protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: AGERA; C19ORF5; CRISP/Cas9 system; HDAC4; LC3; MAP1S; N2a; acetylation; aggregate; apicidin; autophagy; deacetylase; huntingtin; huntington's disease; stability