Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila

Wen, Jung‐Kun; Wang, Yiting; Chan, Chih‐Chiang; Hsieh, Cheng-Wen; Liao, Hsiao-Man; Hung, Chien‐Ching; Chen, Guang-Chao

doi:10.7554/elife.29338

Cited by 50 publications

(54 citation statements)

References 78 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To verify that the categories of ATG gene results were not simply due to variability with hypomorphic RNAi conditions, we examined null mutants for Atg5, Atg9 , and Stx17 (Kim et al, 2016; Wen et al, 2017; Takáts et al, 2013). Consistent with the RNAi results, loss of Atg9 or Stx17 functions fully blocked tAL formation, while Atg5 null mutants only partially reduced the extent of the tubulated network (Figure 3C–H and Figure 3—figure supplement 1C–E).…”

Section: Resultsmentioning

confidence: 99%

An Autophagy-Dependent Tubular Lysosomal Network Synchronizes Degradative Activity Required for Muscle Remodeling

Murakawa

Kiger

Sakamaki

et al. 2020

Preprint

View full text Add to dashboard Cite

Previously, we reported that autophagy is critical for Drosophila muscle remodeling during metamorphosis (Fujita et al., 2017). However, little is known about how lysosomes meet increased degradative demand upon cellular remodeling. Here, we found an extensive tubular autolysosomal network in remodeling muscle. The tubular network transiently appeared and exhibited the capacity to degrade autophagic cargoes. The tubular autolysosomal network was uniquely marked by the autophagic SNARE protein, Syntaxin 17, and its formation depended on both autophagic flux and degradative function, with the exception of the Atg12 and Atg8 ubiquitin-like conjugation systems. Among ATG-deficient mutants, the efficiency of lysosomal tubulation correlated with the phenotypic severity in muscle remodeling. The lumen of the tubular network was continuous and homogeneous across a broad region of the remodeling muscle. Altogether, we revealed that the dynamic expansion of a tubular autolysosomal network synchronizes the abundant degradative activity required for developmentally regulated muscle remodeling.Impact StatementAnalysis of developmentally-regulated Drosophila muscle remodeling revealed autophagy-dependent formation of an extensive, Syntaxin 17-marked, tubular network that synchronizes the abundant degradative activity across a broad region of the remodeling muscle

show abstract

Section: Resultsmentioning

confidence: 99%

An Autophagy-Dependent Tubular Lysosomal Network Synchronizes Degradative Activity Required for Muscle Remodeling

Murakawa

Kiger

Sakamaki

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, the induction of autophagy can block stress-induced ISC proliferation (47). In addition, Atg9 is also required for midgut homeostasis under normal physiological condition, and it specifically acts in enterocytes to control cell growth by limiting TOR signaling (48). Analysis of various Atg genes in the Drosophila midgut has demonstrated that the Atg1 complex components, including Atg1, Atg13, and Atg17, play crucial roles in controlling enterocytes cell growth (48).…”

Section: Atg101 Regulates Both Neuron and Midgut Homeostasismentioning

confidence: 99%

“…In addition, Atg9 is also required for midgut homeostasis under normal physiological condition, and it specifically acts in enterocytes to control cell growth by limiting TOR signaling (48). Analysis of various Atg genes in the Drosophila midgut has demonstrated that the Atg1 complex components, including Atg1, Atg13, and Atg17, play crucial roles in controlling enterocytes cell growth (48). Furthermore, it appears that the Atg1 complex and Atg9 regulate TOR signaling via different mechanisms during enterocyte cell growth (48).…”

Section: Atg101 Regulates Both Neuron and Midgut Homeostasismentioning

confidence: 99%

“…Analysis of various Atg genes in the Drosophila midgut has demonstrated that the Atg1 complex components, including Atg1, Atg13, and Atg17, play crucial roles in controlling enterocytes cell growth (48). Furthermore, it appears that the Atg1 complex and Atg9 regulate TOR signaling via different mechanisms during enterocyte cell growth (48). Interestingly, other core autophagy-related genes, such as Atg7, Atg12, Atg16, Atg18, and Vps32, are not required for enterocyte cell growth in Drosophila adult midguts, indicating that the role of the Atg1 complex and Atg9 in maintaining midgut homeostasis might be specific (48).…”

Section: Atg101 Regulates Both Neuron and Midgut Homeostasismentioning

confidence: 99%

“…Furthermore, it appears that the Atg1 complex and Atg9 regulate TOR signaling via different mechanisms during enterocyte cell growth (48). Interestingly, other core autophagy-related genes, such as Atg7, Atg12, Atg16, Atg18, and Vps32, are not required for enterocyte cell growth in Drosophila adult midguts, indicating that the role of the Atg1 complex and Atg9 in maintaining midgut homeostasis might be specific (48). Consistent with the reported phenotype, upon knocking down Atg1, Atg13, and Atg17, we found that loss of Atg101 caused defects in adult midgut homeostasis and resulted in abnormal midgut mor-…”

Section: Atg101 Regulates Both Neuron and Midgut Homeostasismentioning

confidence: 99%

See 2 more Smart Citations

The autophagy-related gene Atg101 in Drosophila regulates both neuron and midgut homeostasis

Guo

Nan

Miao

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Mike Shipston Atg101 is an autophagy-related gene identified in worms, flies, mice, and mammals, which encodes a protein that functions in autophagosome formation by associating with the ULK1-Atg13-Fip200 complex. In the last few years, the critical role of Atg101 in autophagy has been well-established through biochemical studies and the determination of its protein structure. However, Atg101's physiological role, both during development and in adulthood, remains less understood. Here, we describe the generation and characterization of an Atg101 lossof-function mutant in Drosophila and report on the roles of Atg101 in maintaining tissue homeostasis in both adult brains and midguts. We observed that homozygous or hemizygous Atg101 mutants were semi-lethal, with only some of them surviving into adulthood. Both developmental and starvation-induced autophagy processes were defective in the Atg101 mutant animals, and Atg101 mutant adult flies had a significantly shorter lifespan and displayed a mobility defect. Moreover, we observed the accumulation of ubiquitin-positive aggregates in Atg101 mutant brains, indicating a neuronal defect. Interestingly, Atg101 mutant adult midguts were shorter and thicker and exhibited abnormal morphology with enlarged enterocytes. Detailed analysis also revealed that the differentiation from intestinal stem cells to enterocytes was impaired in these midguts. Cell type-specific rescue experiments disclosed that Atg101 had a function in enterocytes and limited their growth. In summary, the results of our study indicate that Drosophila Atg101 is essential for tissue homeostasis in both adult brains and midguts. We propose that Atg101 may have a role in age-related processes. Autophagy (macroautophagy) is a process in which cytoplasmic materials, including organelles and macromolecules, are delivered to and degraded in the lysosome (1-4). As a major intracellular degradation system, autophagy plays important roles in development, tissue homeostasis, and aging (5-7). Defects in the autophagy pathway cause various human diseases, such as cancer and neurodegenerative diseases (8-10). Genetic studies from budding yeast have identified more than 30 Atg genes, which function at various steps during autophagy (2, 3, 11). Most of these genes are highly conserved from yeast to mammals (3, 11). Among them, the Atg1 complex acts at the initiation stage of autophagy functioning as a scaffold for the recruitment of downstream Atg 2 proteins to the preautophagosomal structure (4, 11-13). The yeast Atg1 complex consists of Atg1, Atg13, Atg17, Atg29, and Atg31, and its mammalian counterpart is composed of ULK1 (or ULK2), Atg13, FIP200 (also known as RB1CC1) and Atg101 (4, 11-13). Mammalian ULK1 and ULK2 are homologs of Atg1 (13). FIP200 is generally considered as a homolog of yeast Atg11 and Atg17 (13). Homologs of Atg29 and Atg31 are not found in higher eukaryotes (13). In contrast, Atg101 is present in most eukaryotes, with the exception of budding yeast (13). It has been proposed that the regu...

show abstract

Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract

et al. 2021

Self Cite

View full text Add to dashboard Cite

Autophagy regulates cellular homeostasis by degrading and recycling cytosolic components and damaged organelles. Disruption of autophagic flux has been shown to induce or facilitate neurodegeneration and accumulation of autophagic vesicles is overt in neurodegenerative diseases. The fruit fly Drosophila has been used as a model system to identify new factors that regulate physiology and disease. Here we provide a historical perspective of how the fly models have offered mechanistic evidence to understand the role of autophagy in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth neuropathy, and polyglutamine disorders. Autophagy also plays a pivotal role in maintaining tissue homeostasis and protecting organism health. The gastrointestinal tract regulates organism health by modulating food intake, energy balance, and immunity. Growing evidence is strengthening the link between autophagy and digestive tract health in recent years. Here, we also discuss how the fly models have advanced the understanding of digestive physiology regulated by autophagy.

show abstract

Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila

Cited by 50 publications

References 78 publications

An Autophagy-Dependent Tubular Lysosomal Network Synchronizes Degradative Activity Required for Muscle Remodeling

An Autophagy-Dependent Tubular Lysosomal Network Synchronizes Degradative Activity Required for Muscle Remodeling

The autophagy-related gene Atg101 in Drosophila regulates both neuron and midgut homeostasis

Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract

Contact Info

Product

Resources

About