title: Huntingtin functions as a scaffold for selective macroautophagy.
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.
authors: 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.
authors: Yan-Ning
authors: YN
authors: Rui
authors: 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.
authors: Zhen
authors: Z
authors: Xu
authors: Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Bindi
authors: B
authors: Patel
authors: 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.
authors: Zhihua
authors: Z
authors: Chen
authors: 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.
authors: Dongsheng
authors: D
authors: Chen
authors: 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.
authors: Antonio
authors: A
authors: Tito
authors: Program in Developmental Biology, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, 1250 Moursund Street Houston, Texas 77030, USA.
authors: Gabriela
authors: G
authors: David
authors: 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.
authors: Yamin
authors: Y
authors: Sun
authors: 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.
authors: Erin F
authors: EF
authors: Stimming
authors: 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.
authors: Hugo J
authors: HJ
authors: Bellen
authors: 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.
authors: Ana Maria
authors: AM
authors: Cuervo
authors: 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.
authors: Sheng
authors: S
authors: Zhang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071189:Autophagy-Related Protein-1 Homolog; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D029721:Drosophila Proteins; C086055:HTT protein, human; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D025801:Ubiquitin; C546842:MTOR protein, human; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human