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...
Myotubularin (MTM) and myotubularin-related (MTMR) lipid phosphatases catalyze the removal of a phosphate group from certain phosphatidylinositol derivatives. Because some of these substrates are required for macroautophagy/autophagy, during which unwanted cytoplasmic constituents are delivered into lysosomes for degradation, MTM and MTMRs function as important regulators of the autophagic process. Despite its physiological and medical significance, the specific role of individual MTMR paralogs in autophagy control remains largely unexplored. Here we examined two Drosophila MTMRs, EDTP and Mtmr6, the fly orthologs of mammalian MTMR14 and MTMR6 to MTMR8, respectively, and found that these enzymes affect the autophagic process in a complex, condition-dependent way. EDTP inhibited basal autophagy, but did not influence stress-induced autophagy. In contrast, Mtmr6 promoted the process under nutrient-rich settings, but effectively blocked its hyperactivation in response to stress. Thus, Mtmr6 is the first identified MTMR phosphatase with dual, antagonistic roles in the regulation of autophagy, and shows conditional antagonism/synergism with EDTP in modulating autophagic breakdown. These results provide a deeper insight into the adjustment of autophagy.
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