Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging

Kim, Myung-Jin; Park, Hae Li; Park, Hwan‐Woo; Ro, Seung Hyun; Nam, Samuel G.; Reed, John M.; Guan, Jun; Lee, Jun Hee

doi:10.4161/auto.24811

Cited by 54 publications

(58 citation statements)

References 75 publications

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“…These observations indicate that HTT-deficient Drosophila are unable to mount a stress-induced autophagic response. This phenotype is similar to that reported for LOF mutants of Drosophila RB1CC1/ FIP200 and Atg7, proteins that are also essential for autophagy (17)(18)(19). In addition, we observed a climbing deficit in HTT LOF larvae, a behavioral defect typical of impaired autophagy.…”

Section: Resultssupporting

confidence: 89%

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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.

258

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: Resultssupporting

confidence: 89%

“…1C). This behavior is similar to the motor deficit reported for RB1CC1/FIP200 and Atg7 LOF mutants (17,18). These data demonstrate that loss of HTT in Drosophila results in an almost complete loss of starvationinduced autophagy.…”

Section: Resultssupporting

confidence: 86%

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.

258

228

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“…In C. elegans, the uncoordinated movement observed for the unc-51 mutant is not observed for the epg-1 (atg13) (37) and epg-9 (atg101) mutants (38). Similarly, in Drosophila melanogaster, neuronal defects observed in the unc-51 mutant are not observed in the Fip200 mutant (69). In addition to effects on the nervous system, the findings of a recent study suggest that ULK1 but not Atg13 and FIP200 regulates melanogenesis in cultured cells (70).…”

Section: Discussionmentioning

confidence: 96%

Atg13 Is Essential for Autophagy and Cardiac Development in Mice

Kaizuka

Mizushima

2016

Molecular and Cellular Biology

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Autophagy is a major intracellular degradation system by which cytoplasmic components are enclosed by autophagosomes and delivered to lysosomes. Formation of the autophagosome requires a set of autophagy-related (Atg) proteins. Among these proteins, the ULK1 complex, which is composed of ULK1 (or ULK2), FIP200, Atg13, and Atg101, acts at an initial step. Previous studies showed that ULK1 and FIP200 also function in pathways other than autophagy. However, whether Atg13 and Atg101 act similarly to ULK1 and FIP200 remains unknown. In the present study, we generated Atg13 knockout mice. Like FIP200-deficient mice, Atg13-deficient mice die in utero, which is distinct from most other types of Atg-deficient mice. Atg13-deficient embryos show growth retardation and myocardial growth defects. In cultured fibroblasts, Atg13 deficiency blocks autophagosome formation at an upstream step. In addition, sensitivity to tumor necrosis factor alpha (TNF-␣)-induced apoptosis is enhanced by deletion of Atg13 or FIP200, but not by other Atg proteins, as well as by simultaneous deletion of ULK1 and ULK2. These results suggest that Atg13 has both autophagic and nonautophagic functions and that the latter are essential for cardiac development and likely shared with FIP200 but not with ULK1/2.

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“…It is formerly reported that, under the conditions of autophagy inhibition, there is compensatory upregulation of Atg1 protein expression. 11,18 Thus, it is possible that Gyf silencing inhibited autophagy. In contrast, Atg1 silencing (positive control) strongly reduced the Atg1 expression level as expected ( Fig.…”

Section: Identification Of Gyf/cg11148 As a New Autophagyregulating Genementioning

confidence: 99%

“…It has been formerly shown that Atg1 regulates neuronal development independent of its autophagy-regulating activities. [18][19][20][21] Therefore, it is possible that, although Gyf is required for Atg1-Atg13-induced autophagic eye degeneration, it does not play a critical role in regulating Atg1's neuronal morphogenesis-regulating activities. .…”

Section: Identification Of Gyf/cg11148 As a New Autophagyregulating Genementioning

confidence: 99%

Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis

et al. 2015

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Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging

Abstract: these authors contributed equally to this work.

Cited by 54 publications

References 75 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

Atg13 Is Essential for Autophagy and Cardiac Development in Mice

Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis

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