Programmed cell death plays an important role during animal development, and defects in this process result in a variety of human disorders including cancer, neurodegeneration and autoimmunity. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. The regulation of apoptosis is relatively well understood, but little is known about the mechanisms that mediate autophagic programmed cell death. We are studying steroid-activated autophagic cell death in Drosophila, and are using the midgut of the larval intestine as a model. An increase in steroid triggers a genetic program that activates midgut cell death. These developmentally-regulated cell deaths do not depend on apoptosis genes, including caspase proteases, and they possess the morphology of cells that die by autophagic cell death. Significantly, autophagy (Atg) genes are required for midgut degradation where they regulate programmed cell size reduction. While much is known about the function and regulation of macro-autophagy (autophagy) in yeast, less is known about the mechanisms that regulate this process in animal cells in vivo, and little is known about the function of autophagy during cell death. It has been assumed that the mechanisms controlling autophagy are identical between yeast and humans. Our hypothesis is that the cell-specific use of autophagy in multicellular organisms involves previously unrecognized regulatory mechanisms that integrate with core autophagy pathways. In support of this hypothesis, we have discovered that the conserved E1 and E2 enzymes encoded by Atg7and Atg3 are not required for autophagy and degradation of the fly midgut, while these genes are required for starvation-triggered autophagy in flies. By contrast, autophagy in midgut cells depends on Uba1, the E1 used for ubiquitination. These and other data indicate that we have discovered a novel mechanism by which ubiquitin regulates Atg7 and Atg3-independent autophagy, and our goal is to characterize molecular mechanisms that control autophagy during midgut cell death. Here we propose to: (1) investigate the role of Atg8 in midgut autophagy and cell size reduction, (2) determine the role of ubiquitin-binding proteins and Parkin substrates in autophagy, and (3) characterize new genes that are required for clearance of mitochondria and autophagy. The recent association of autophagy with neurodegenerative disorders and cancer indicates the importance of investigating the understudied role of autophagy during programmed cell death.

Public Health Relevance

Programmed cell death plays an important role during animal development, and defects in this process are associated with a variety of human disorders including cancer and autoimmunity. We are studying the relationship between autophagy and programmed cell death during development. The recent association of autophagy with neurodegenerative disorders and cancer illustrates the importance of investigating the relationship between autophagy and cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111658-03
Application #
9213379
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2015-03-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$286,425
Indirect Cost
$115,425
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Anding, Allyson L; Baehrecke, Eric H (2017) Cleaning House: Selective Autophagy of Organelles. Dev Cell 41:10-22
Lindqvist, L M; Simon, A K; Baehrecke, E H (2015) Current questions and possible controversies in autophagy. Cell Death Discov 1:
Zhang, Hong; Baehrecke, Eric H (2015) Eaten alive: novel insights into autophagy from multicellular model systems. Trends Cell Biol 25:376-87
Anding, Allyson L; Baehrecke, Eric H (2015) Autophagy in Cell Life and Cell Death. Curr Top Dev Biol 114:67-91
Galluzzi, Lorenzo; Pietrocola, Federico; Bravo-San Pedro, José Manuel et al. (2015) Autophagy in malignant transformation and cancer progression. EMBO J 34:856-80