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Potential function for the Huntingtin protein as a scaffold for selective autophagy.

  • Author(s): Ochaba, Joseph
  • Lukacsovich, Tamás
  • Csikos, George
  • Zheng, Shuqiu
  • Margulis, Julia
  • Salazar, Lisa
  • Mao, Kai
  • Lau, Alice L
  • Yeung, Sylvia Y
  • Humbert, Sandrine
  • Saudou, Frédéric
  • Klionsky, Daniel J
  • Finkbeiner, Steven
  • Zeitlin, Scott O
  • Marsh, J Lawrence
  • Housman, David E
  • Thompson, Leslie M
  • Steffan, Joan S
  • et al.
Abstract

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.

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