Phosphorylation of Serine 114 on Atg32 mediates mitophagy

Aoki, Yoshimasa; Kanki, Tomotake; Hirota, Yuko; Kurihara, Yusuke; Saigusa, Toyohei; Uchiumi, Takeshi; Kang, Dongchon

doi:10.1091/mbc.e11-02-0145

Cited by 207 publications

(280 citation statements)

References 51 publications

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“…2A). To test for interaction with members of this complex, a minimal fragment of the C-terminal domain of HTT (amino acids 2416-3144) that contains the Atg11 CC3-and CC4-like domains involved in interactions with autophagy proteins (28,29), was fused in frame to an N-terminal Venus tag (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

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

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

252

228

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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 starvationinduced 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.rodegenerative disorder caused by an expansion of a CAG trinucleotide repeat encoding a polyglutamine (polyQ) tract near the N terminus of the 350-kD Huntingtin protein (HTT) (1). Identifying the normal biological function of the HTT protein is important in the effort to design and implement effective therapeutic interventions for HD, but has proved challenging.In the mouse, loss of HTT leads to lethality during gastrulation at embryonic day 7 (2-4). Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7-9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.In contrast to the embryonic lethality observed in the mouse, Drosophila lacking the endogenous Htt gene develop normally. However, adult Drosophila HTT loss-of-function (LOF) flies show an accelerated neurodege...

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Section: Resultsmentioning

confidence: 99%

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

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

252

228

View full text Add to dashboard Cite

show abstract

“…In addition, phosphorylation of these receptors is one mechanism to regulate mitophagy. For example, phosphorylation of Atg32 at residue serine 114 is necessary for its interaction with the adaptor protein Atg11, which recruits core ATGs to form autophagosomes that engulf mitochondria 34 . Similarly, the phosphorylation of serine residues flanking the LIR motif of BNIP3 promotes the binding of BNIP3 to LC3B and Golgi-associated ATPase enhancer of 16 kDa (GATE16; another Atg8 orthologue), thus facilitating mitophagy 35 .…”

Section: Box 1 | Autophagy and Protein Quality Controlmentioning

confidence: 99%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

822

801

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“…Atg32 is a transmembrane protein residing in the outer mitochondrial membrane. Atg32 is phosphorylated (Aoki et al 2011) and the interaction with Atg11 occurs only under conditions that induce mitophagy. Thus, an unknown alteration, perhaps in Atg32 conformation or the phosphorylation-dependent generation of a binding motif, presumably leads to its activation.…”

Section: Macroautophagymentioning

confidence: 99%

Autophagic Processes in Yeast: Mechanism, Machinery and Regulation

2013

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Autophagy refers to a group of processes that involve degradation of cytoplasmic components including cytosol, macromolecular complexes, and organelles, within the vacuole or the lysosome of higher eukaryotes. The various types of autophagy have attracted increasing attention for at least two reasons. First, autophagy provides a compelling example of dynamic rearrangements of subcellular membranes involving issues of protein trafficking and organelle identity, and thus it is fascinating for researchers interested in questions pertinent to basic cell biology. Second, autophagy plays a central role in normal development and cell homeostasis, and, as a result, autophagic dysfunctions are associated with a range of illnesses including cancer, diabetes, myopathies, some types of neurodegeneration, and liver and heart diseases. That said, this review focuses on autophagy in yeast. Many aspects of autophagy are conserved from yeast to human; in particular, this applies to the gene products mediating these pathways as well as some of the signaling cascades regulating it, so that the information we relate is relevant to higher eukaryotes. Indeed, as with many cellular pathways, the initial molecular insights were made possible due to genetic studies in Saccharomyces cerevisiae and other fungi. TABLE OF CONTENTS Abstract 341Introduction 342

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Phosphorylation of Serine 114 on Atg32 mediates mitophagy

Cited by 207 publications

References 51 publications

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

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

Autophagy at the crossroads of catabolism and anabolism

Autophagic Processes in Yeast: Mechanism, Machinery and Regulation

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