Potential function for the Huntingtin protein as a scaffold for selective autophagy.
Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvation-induced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
Joseph
J
Ochaba
Department of Developmental and Cell Biology.
Tamás
T
Lukacsovich
Department of Anatomy, Cell, and Developmental Biology, Eötvös Loránd University, H-1117 Budapest, Hungary;
George
G
Csikos
Department of Neuroscience, University of Virginia, Charlottesville, VA 22908;
Shuqiu
S
Zheng
Department of Neurology and Department of Physiology, Gladstone Institute of Neurological Disease, Taube-Koret Center for Huntington's Disease Research, University of California, San Francisco, CA 94158;
Julia
J
Margulis
Department of Psychiatry and Human Behavior.
Lisa
L
Salazar
Department of Molecular, Cellular, and Developmental Biology, and Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;
Kai
K
Mao
Department of Psychiatry and Human Behavior.
Alice L
AL
Lau
Department of Psychiatry and Human Behavior.
Sylvia Y
SY
Yeung
Institut Curie, Orsay 91405, France; and.
Sandrine
S
Humbert
Institut Curie, Orsay 91405, France; and.
Frédéric
F
Saudou
Department of Molecular, Cellular, and Developmental Biology, and Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;
Daniel J
DJ
Klionsky
Department of Neurology and Department of Physiology, Gladstone Institute of Neurological Disease, Taube-Koret Center for Huntington's Disease Research, University of California, San Francisco, CA 94158;
Steven
S
Finkbeiner
Department of Neuroscience, University of Virginia, Charlottesville, VA 22908;
Scott O
SO
Zeitlin
Department of Developmental and Cell Biology.
J Lawrence
JL
Marsh
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 dhousman@mit.edu jssteffa@uci.edu.
David E
DE
Housman
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; Department of Psychiatry and Human Behavior.
Leslie M
LM
Thompson
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; Department of Psychiatry and Human Behavior, dhousman@mit.edu jssteffa@uci.edu.
Joan S
JS
Steffan
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy; D004330:Drosophila; D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*
D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins
Huntingtin; Huntington disease; neurodegeneration; polyglutamine; selective autophagy