Autophagy literally means """"""""self-eating"""""""" at the subcellular level. In the same way that your body breaks down fat and protein reserves if starved for a long enough time, the cell does the same thing, delivering cytoplasm to the lysosome/vacuole for degradation and recycling of the resulting macromolecules. Autophagy occurs in all eukaryotes and the protein components of the autophagic machinery are conserved from yeast to mammals. The hallmark of this process is the formation of double-membrane cytosolic vesicles, autophagosomes that sequester cytoplasm. After completion, the autophagosomes fuse with the lysosome/vacuole to release the inner vesicle that is broken down, allowing access to the cargo. Autophagy is a starvation response, but it also plays a role in various developmental processes and is associated with a range of pathophysiological conditions: Defects in autophagy can lead to some types of cancer, heart disease and neurodegeneration including Alzheimer's, Parkinson's and Huntington's diseases. Autophagy is also involved in innate immunity, in eliminating invading pathogenic bacteria and viruses and in lifespan extension. Autophagy can be non-specific;however, specific types of autophagy play a role in various processes including the removal of damaged or superfluous organelles, and the elimination of certain pathogens. The cytoplasm to vacuole targeting pathway is another example of specific autophagy. There are many questions about autophagy that remain to be answered. For example, we want to determine how environmental signals are transduced into an autophagic response, what regulatory controls determine the switch between specific and non-specific types of autophagy, the mechanism of achieving cargo specificity, the origin of the sequestering vesicle membrane and the molecular details of vesicle formation. We are using yeast to investigate the molecular mechanism of autophagy;this is the best system for a molecular genetic and biochemical analysis of this complex process. Because of the high degree of conservation, however, the information we learn from yeast will be applicable to higher eukaryotes. At present, we have characterized over twenty autophagy-related (Atg) proteins, determining their location and stage of action in the autophagy process. We are now defining specific interaction domains, and assigning a temporal order of action to the proteins with the ultimate goal of understanding their biochemical function. We have also established an in vivo reconstitution system that will allow us to define the functions and characteristics of individual Atg proteins. This knowledge will provide important information about basic cell biological processes including the mechanisms that govern dynamic membrane rearrangements, and allow specific recognition of subcellular components essential aspects required to maintain discrete organelles. A full understanding of autophagy may also allow therapeutic modulation of a process that is implicated in a range of disease conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053396-21
Application #
7844879
Study Section
Cell Structure and Function (CSF)
Program Officer
Ainsztein, Alexandra M
Project Start
1991-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
21
Fiscal Year
2010
Total Cost
$705,233
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Organized Research Units
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Klionsky, Daniel J (2017) Does relevancy matter? Biochem Mol Biol Educ 45:377-378
Sasaki, Tomoyuki; Lian, Shanshan; Khan, Alam et al. (2017) Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase. Autophagy 13:386-403
Levine, Beth; Klionsky, Daniel J (2017) Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research. Proc Natl Acad Sci U S A 114:201-205
Loos, Ben; Klionsky, Daniel J; Wong, Esther (2017) Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging. Prog Neurobiol 156:90-106
Yao, Zhiyuan; Liu, Xu; Klionsky, Daniel J (2017) MitoPho8?60 Assay as a Tool to Quantitatively Measure Mitophagy Activity. Methods Mol Biol :
Feng, Yuchen; Klionsky, Daniel J (2017) Autophagic membrane delivery through ATG9. Cell Res 27:161-162
Mao, Kai; Klionsky, Daniel J (2017) Xenophagy: A battlefield between host and microbe, and a possible avenue for cancer treatment. Autophagy 13:223-224
Popelka, Hana; Damasio, Alejandro; Hinshaw, Jenny E et al. (2017) Structure and function of yeast Atg20, a sorting nexin that facilitates autophagy induction. Proc Natl Acad Sci U S A 114:E10112-E10121
Nanji, Tamiza; Liu, Xu; Chew, Leon H et al. (2017) Conserved and unique features of the fission yeast core Atg1 complex. Autophagy :1-10
Eapen, Vinay V; Waterman, David P; Bernard, Amélie et al. (2017) A pathway of targeted autophagy is induced by DNA damage in budding yeast. Proc Natl Acad Sci U S A 114:E1158-E1167

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