Huntingtin functions as a scaffold for selective macroautophagy

Rui, Yanning; Xu, Zhen; Patel, Bindi; Chen, Zhihua; Chen, Dongsheng; Tito, Antonio; David, Gabriela; Sun, Yamin; Stimming, Erin Furr; Bellen, Hugo J.; Cuervo, Ana María; Zhang, Sheng

doi:10.1038/ncb3101

Cited by 357 publications

(365 citation statements)

References 82 publications

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“…However, the underlying mechanism is yet to be uncovered. Recently, Huntingtin, the Huntington's disease gene product, was identifi ed as a scaffold protein for selective autophagy including aggrephagy, mitophagy, and lipophagy in mammalian cells, paving the way for further investigation in this emerging young field [8] . In addition, cargo receptor proteins such as p62 and NBR1 bring cargos to autophagosomes by interacting with the autophagosomal protein LC3 [9] .…”

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confidence: 99%

Selective role of autophagy in neuronal function and neurodegenerative diseases

Rui

2015

Neurosci. Bull.

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·Editorial·Proteostasis is critical for neuronal maintenance and survival, and its imbalance leads to neurodegeneration with the hallmark of protein misfolding and aggregation [1] .Macroautophagy becomes a major route for the clearance of protein aggregates that are normally poor substrates for the proteasome, the other protein quality-control machinery [2] . As a fl ux process, macroautophagy (hereafter referred to as autophagy) involves the formation of the autophagosome, a double-membrane vesicle for engulfi ng unwanted cellular components such as protein aggregates, and the fusion of autophagosomes with lysosomes that contain many potent proteases for fi nal degradation [3] .In the past decades, the mechanism of autophagy has been intensively studied under starvation conditions. Autophagy is a hierarchical process involving the activation of ULK1, the initiating kinase, and many downstream events such as Beclin 1 complex activation and LC3 lipidation [3] . It has been well established that, during amino-acid starvation, mTOR, the master nutrient sensor, dissociates from and in turn activates ULK1 kinase [4] .Interestingly, upon energy starvation such as glucose depletion, the main energy sensor AMPK activates ULK1 through antagonizing mTOR-mediated ULK1 inhibitory phosphorylation [5] . It is generally believed that starvation induces non-selective autophagy that targets non-essential cellular components for degradation to provide building blocks for cellular survival in unfavorable conditions.In comparison with the well-characterized starvationinduced nonselective autophagy, the molecular mechanism of selective autophagy is largely unknown [6] . Selective autophagy is a comprehensive term that can be classifi ed into many different types such as aggrephagy, mitophagy, and lipophagy [7] . In particular, aggrephagy plays an important role in neuronal survival, as neurons are nondividing cells and cannot overcome cellular toxicity induced by protein aggregates through dilution effects. Therefore, aggrephagy becomes essential for neurons to preserve proteostasis. However, the underlying mechanism is yet to be uncovered. Recently, Huntingtin, the Huntington's disease gene product, was identifi ed as a scaffold protein for selective autophagy including aggrephagy, mitophagy, and lipophagy in mammalian cells, paving the way for further investigation in this emerging young field [8] . In addition, cargo receptor proteins such as p62 and NBR1 bring cargos to autophagosomes by interacting with the autophagosomal protein LC3 [9] . As both p62 and NBR1 contain ubiquitin-binding domains, the cargos modifi ed by lineage-specific ubiquitin play an important role in cargo recognition in selective autophagy. For instance, ubiquitin K63-modified substrates preferentially bind to p62 for autophagic degradation [10] .Selective autophagy has been linked to a variety of human diseases including but not limited to neurodegeneration and cancer [11] . For example, tau protein, implicated in Alzheimer's disease (AD), was shown to be ...

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Selective role of autophagy in neuronal function and neurodegenerative diseases

Rui

2015

Neurosci. Bull.

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“…65 In addition, a new study reported that WT-HTT serves as an important scaffold protein in multiple types of selective macroautophagy (not including starvation-induced autophagy) in Drosophila and mammalian cells (including mouse embryonic fibroblasts and striatal cells). 66 WT-HTT is able to bind simultaneously two important ATG proteins, p62 and unc-51-like autophagy activating kinase (ULK1). 66 In sum, studies to date indicate abnormal autophagy function in HD and suggest that HTT has a functional role in autophagy.…”

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“…66 WT-HTT is able to bind simultaneously two important ATG proteins, p62 and unc-51-like autophagy activating kinase (ULK1). 66 In sum, studies to date indicate abnormal autophagy function in HD and suggest that HTT has a functional role in autophagy. Upregulation of autophagy has been shown to enhance polyQ-HTT clearance 53 and drugs targeting autophagy--such as rapamycin/CCI-779, lithium, trehalose and rilmenidine--continue to be of interest as potential therapeutic agents for HD.…”

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confidence: 99%

Primary cilia and autophagic dysfunction in Huntington’s disease

2015

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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology. Indeed, multiple lines of research have identified abnormal autophagy in HD, characterized generally by increased autophagic induction and inefficient clearance of substrates. To date, the origin of autophagic dysfunction in HD remains unclear and the search for actors involved continues. To that end, recent studies have suggested a bidirectional relationship between autophagy and primary cilia, signaling organelles of most mammalian cells. Interestingly, primary cilia structure is defective in HD, suggesting a potential link between autophagic dysfunction, primary cilia and HD pathogenesis. In addition, because polyQ-HTT also accumulates in primary cilia, the possibility exists that primary cilia might play additional roles in HD: perhaps by disrupting signaling pathways or acting as a reservoir for secretion and propagation of toxic, misfolded polyQ-HTT fragments. Here, we review recent research suggesting potential links between autophagy, primary cilia and HD and speculate on possible pathogenic mechanisms and future directions for the field.

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“…HTT is a scaffolding protein that is involved in multiple cellular functions [65,81,82]. The generation and characterization of Htt knock-out mice revealed that Htt has an essential function during early embryonic development [83][84][85].…”

Section: Wild Type Huntington Functionsmentioning

confidence: 99%

“…HTT has been shown to promote selective macroautophagy through its interaction with several autophagy pathway members including p62/SQSTM1 (p62), Ubiquitin (Ub) and microtubule associated protein 1A/1B-light chain 3 (LC3) [81]. "Bulk" non-selective macroautophagy (a.k.a.…”

Section: Wild Type Huntington Functionsmentioning

confidence: 99%

Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

André¹

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Huntington's disease (HD) is a neurodegenerative disorder that effects up to 1 in every 10,000 people and it is caused by an expansion of the polyglutamine (polyQ) stretch within the Huntingtin (HTT) protein [1]. The HTT polyQ in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR) [2][3][4]. The PRR is a binding site for many , and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles [8,9]. iv Acknowledgements I would first and foremost like to thank Scott Zeitlin and Jeh-Ping Liu for their scientific guidance, technical expertise and continual support. Thank you for always pushing me to be a better scientist, and for your patience during the times when things were not working out the way we wanted. I would also like to thank my committee

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Huntingtin functions as a scaffold for selective macroautophagy

Cited by 357 publications

References 82 publications

Selective role of autophagy in neuronal function and neurodegenerative diseases

Selective role of autophagy in neuronal function and neurodegenerative diseases

Primary cilia and autophagic dysfunction in Huntington’s disease

Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

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