Huntingtin functions as a scaffold for selective macroautophagy

Yan-Ning Rui; Zhen Xu; Bindi Patel; Zhihua Chen; Dongsheng Chen; Antonio Tito; Gabriela David; Yamin Sun; Erin F Stimming; Hugo J Bellen; Ana Maria Cuervo; Sheng Zhang

doi:10.1038/ncb3101

Huntingtin functions as a scaffold for selective macroautophagy

Nat Cell Biol. 2015 Mar;17(3):262-75. doi: 10.1038/ncb3101. Epub 2015 Feb 16.

Authors

Affiliations

¹ The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA.
² Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
³ 1] The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA [2] Programs in Human and Molecular Genetics and Neuroscience, The University of Texas Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA.
⁴ Program in Developmental Biology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, 1250 Moursund Street Houston, Texas 77030, USA.
⁵ Department of Neurology, The University of Texas Medical School at Houston, The University of Texas Health Science Center at Houston (UTHealth), 6341 Fannin Street Houston, Texas 77030, USA.
⁶ 1] Program in Developmental Biology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, 1250 Moursund Street Houston, Texas 77030, USA [2] Howard Hughes Medical Institute, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, 1250 Moursund Street Houston, Texas 77030, USA [3] Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, 1250 Moursund Street Houston, Texas 77030, USA.
⁷ 1] Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA [3] Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
⁸ 1] The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA [2] Programs in Human and Molecular Genetics and Neuroscience, The University of Texas Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA [3] Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, The University of Texas Health Science Center at Houston (UTHealth), 1825 Pressler Street Houston, Texas 77030, USA.

PMID: 25686248
PMCID: PMC4344873
DOI: 10.1038/ncb3101

Abstract

Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy. In Drosophila, Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates. Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR. Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / genetics*
Autophagy-Related Protein-1 Homolog
Drosophila Proteins
Drosophila melanogaster / genetics*
Drosophila melanogaster / metabolism
Gene Expression Regulation
HEK293 Cells
HeLa Cells
Humans
Huntingtin Protein
Intracellular Signaling Peptides and Proteins / genetics*
Intracellular Signaling Peptides and Proteins / metabolism
Microtubule-Associated Proteins / genetics*
Microtubule-Associated Proteins / metabolism
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Phagosomes / metabolism
Protein Binding
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
RNA-Binding Proteins
Signal Transduction
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Ubiquitin / genetics
Ubiquitin / metabolism
Ubiquitination

Substances

Drosophila Proteins
HTT protein, human
Htt protein, Drosophila
Huntingtin Protein
Intracellular Signaling Peptides and Proteins
MAP1LC3A protein, human
Microtubule-Associated Proteins
Nerve Tissue Proteins
P62 protein, human
RNA-Binding Proteins
Ubiquitin
MTOR protein, human
Autophagy-Related Protein-1 Homolog
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
ULK1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding