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

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...

Ausführliche Beschreibung

Bibliographische Detailangaben
Hauptverfasser: Ochaba, Joseph, Csikos, George, Zheng, Shuqiu, Margulis, Julia, Salazar, Lisa, Mao, Kai, Lau, Alice L., Yeung, Sylvia Y., Humbert, Sandrine, Klionsky, Daniel J., Finkbeiner, Steven, Zeitlin, Scott O., Marsh, J. Lawrence, Thompson, Leslie M., Steffan, Joan S., Lukacsovich, Tamas, Saudou, Frederic, Housman, David E
Weitere Verfasser: Massachusetts Institute of Technology. Department of Biology
Format: Artikel
Sprache:en_US
Veröffentlicht: National Academy of Sciences (U.S.) 2015
Online Zugang:http://hdl.handle.net/1721.1/97246
https://orcid.org/0000-0001-5016-0756
Beschreibung
Zusammenfassung: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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