Uba1 functions in Atg7- and Atg3-independent autophagy

Chang, Tsun-Kai; Shravage, Bhupendra V.; Hayes, Sebastian; Powers, Christine; Simin, Rachel T.; Harper, J. Wade; Baehrecke, Eric H.

doi:10.1038/ncb2804

Cited by 166 publications

(201 citation statements)

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“…This agrees with previous data showing that suppression of other core autophagy genes such as Atg1 26 blocks H 2 O 2 -induced autophagy in the intestine. Importantly, like other genes involved in the autophagic pathway, 17,23,26,35 we were also able to demonstrate the significance of Vps15 in developmentally programmed autophagy. In the Drosophila intestine, Vps15 was shown to be necessary for programmed cell size Figure 5 Vps15 is required for developmentally programmed autophagy in the fat body.…”

Section: Discussionsupporting

confidence: 53%

“…21,[23][24][25] The length of the Drosophila midgut decreases drastically in the dying larval intestine at the onset of puparium formation, and this structural change relies on an autophagy-dependent programmed cell size reduction. 26 To determine whether Vps15 is required for programmed cell size reduction, we clonally knocked down the function of Vps15 and examined size in the midgut of animals 2 h after puparium formation (APF). Unlike their neighboring control cells that decreased in cell size in the pupal transition, Figure S3).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the midgut was examined at puparium formation (0 h APF), a stage of development in which autophagy is known to occur. 26 Steroid-activated programmed cell death of Drosophila salivary glands also requires autophagy in addition to the activation of caspases. 23 The larval salivary glands of Drosophila undergo programmed cell death 14-16 h after puparium formation, resulting in no visible gland remnants by 24 h after puparium formation.…”

Section: Resultsmentioning

confidence: 99%

“…Statistical significance was determined using a chi-squared test Vps15 is required for autophagy AL Anding and EH Baehrecke different forms of autophagy could involve unique regulatory pathways. 26,33,34 Thus, it is important to characterize the role of autophagy-related molecules according to the type of autophagy in which they are involved and in a tissue-specific manner.…”

Section: Discussionmentioning

confidence: 99%

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Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

Anding

Baehrecke

2014

Cell Death Differ

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Autophagy is a catabolic process used to deliver cellular material to the lysosome for degradation. The core Vps34/class III phosphatidylinositol 3-kinase (PI3K) complex, consisting of Atg6, Vps15, and Vps34, is highly conserved throughout evolution, critical for recruiting autophagy-related proteins to the preautophagosomal structure and for other vesicular trafficking processes, including vacuolar protein sorting. Atg6 and Vps34 have been well characterized, but the Vps15 kinase remains poorly characterized with most studies focusing on nutrient deprivation-induced autophagy. Here, we investigate the function of Vps15 in different cellular contexts and find that it is necessary for both stress-induced and developmentally programmed autophagy in various tissues in Drosophila melanogaster. Vps15 is required for autophagy that is induced by multiple forms of stress, including nutrient deprivation, hypoxia, and oxidative stress. Furthermore, autophagy that is triggered by physiological stimuli during development in the fat body, intestine, and salivary gland also require the function of Vps15. In addition, we show that Vps15 is necessary for efficient salivary gland protein secretion. These data illustrate the broad importance of Vps15 in multiple forms of autophagy in different animal cells, and also highlight the pleiotropic function of this kinase in multiple vesicle-trafficking pathways. Cell Death and Differentiation ( Autophagy is an evolutionarily conserved process in which cytoplasmic proteins or organelles are packaged into lysosomes for degradation. This process can be initiated by a variety of stimuli, such as high levels of starvation or stress, to provide nutrients to the cells or to clear the cell of damaged organelles or protein aggregates. 1 In some circumstances, autophagy can promote an alternative form of cell death, such as in the clearance of larval tissues in Drosophila melanogaster. 2 As defects in autophagy have been implicated in several physiological and pathological conditions, such as cancer, neurodegenerative diseases, and aging, 3,4 it is important to obtain a complete understanding of the molecular mechanisms controlling autophagy.The induction of autophagy is regulated by the Atg1/Ulk1 complex, and this complex is regulated by mechanistic target of rapamycin (mTOR). 5 Vesicle nucleation is controlled by the class III phosphoinositide 3-kinase (PI3K) complex that generates phosphatidylinositol 3-phosphate (PI3P). 6 This conserved complex consists of vacuolar protein sorting 34 (Vps34; also known as Pik3c3), Atg6/Becn1 (also known as Vps30 in yeast), and the serine-threonine kinase Vps15/ird1 (p150 in mammals; also known as Pik3r4). 7,8 Localized production of PI3P by Vps34 can act to recruit proteins containing PX or FYVE domains to membrane compartments, such as the autophagosome isolation membrane. 9 Vps34 is also required more broadly for several vesicular trafficking processes such as the sorting of hydrolytic enzymes to the yeast vacuole and mammalian lysosome, and endocytic tra...

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Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

Anding

Baehrecke

2014

Cell Death Differ

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“…but Uba1 is indispensable for autophagy and reduction of cell size in Drosophila. 34 Since all cell migration, differentiation, proliferation and cell death are extremely active in embryonic gastrulation, it is speculated that autophagy might be involved the developmental process in the special period as well. However, until recently, almost no solid experimental evidence has been in literature.…”

Section: Discussionmentioning

confidence: 99%

Autophagy functions on EMT in gastrulation of avian embryo

Wang

et al. 2014

Cell Cycle

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y These authors contributed equally to this work.Keywords: autophagy, Atg7, EMT and chick embryo, gastrulation Abbreviations: 3-MA, 3-Methyladenine; BF, bright-field; DAPI, 49-6-Diamidino-2-phenylindole; EB, embryoid bodies; E-Cad, E-cadherin; EMTs, epithelial-mesenchymal transitions; GFP, green fluorescent protein; HN, Hensen's node; MAPILC3(LC3), microtubule-associated protein 1 light chain 3; mTOR, mammalian target of rapamycin; N-Cad, N-cadherin; NT, neural tube; PBS, phosphate-buffered saline; PCD, Programmed cell death; PD, idiopathic Parkinson's Disease; PI3K, phosphoinositide-3-kinase; PPIA, peptidylprolyl isomerase A; PS, primitive streak; RAPA, Rapamycin; RT-PCR, reverse transcription PCR; shh, sonic hedgehog.Autophagy is important for cell renewing for its contribution to the degradation of bulk cytoplasm, long-lived proteins, and entire organelles and its role in embryonic development is largely unknown. In our study, we investigated the function of autophagy in gastrulation of the chick embryo using both in vivo and in vitro approaches, especially in the EMT process, and we found that autophagy gene Atg7 was expressed on the apical side of the ectoderm and endoderm. Over-expression of Atg7 could enhance the expression of Atg8 and the E-cadherin, the latter of which is a crucial marker of the EMT process. We also found that the disturbance of autophagy could retard the development of chick embryos in HH4 with shorter primitive steak than that in the control group, which is a newly formed structure during EMT process. So we assumed that autophagy could affect EMT process by adhesion molecule expression. Moreover, more molecules, such as slug, chordin, shh et., which were all involved in EMT process, were detected to address the mechanism of this phenomena. We established that the inhibition of autophagy could cause developmental delay by affecting EMT process in gastrulation of chick embryos.

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Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors

Stevens,

Wang,

Bouley

et al. 2024

Molecular Oncology

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Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen‐activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1‐deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1‐deficient Drosophila cells. When further investigating autophagy‐related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1‐deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1‐deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1‐deficient cell viability. In conclusion, NF1‐deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1‐associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.

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Uba1 functions in Atg7- and Atg3-independent autophagy

Cited by 166 publications

References 40 publications

Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila

Autophagy functions on EMT in gastrulation of avian embryo

Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors

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