The degradation of membrane proteins via the multivesicular body (MVB) pathway plays an essential role in regulating cell-surface proteins. As a consequence, numerous cellular functions, such as nutrient uptake, cell- cell communication and immune response are dependent on MVBs. The formation of MVBs is executed by a group of highly conserved protein complexes called ESCRTs (Endosomal Sorting Complex Required for Transport). ESCRTs perform a unique membrane budding event, which results in vesicle formation in the lumen of the MVB. Retroviruses, such as HIV, co-opt the ESCRT machinery during viral infection to complete formation of viral particles via a similar membrane budding event at the plasma membrane. Furthermore, cytokinesis requires the ESCRT-dependent fusion of the plasma membrane in order to form two separate cells. Our recent studies indicate that ESCRT function and protein translation are tightly connected. On one hand, the MVB pathway degrades proteins and recycles amino acids for further use in protein translation. On the other hand, we observed that translation efficiency regulates ESCRT function by increasing or decreasing the cellular levels of the ESCRT regulatory protein Ist1. High amino acid levels in the cell increase translation and thus the cellular concentration of Ist1, which in turn decreases ESCRT activity and protein degradation via the MVB pathway. In contrast, starvation induces protein degradation via the MVB pathway by lowering Ist1 levels and by increasing endocytosis of numerous plasma membrane proteins. In addition, we observed that amino acid starvation resulted in the relocalization of some ESCRT components and translation-initiation factors to a filamentous structure, which we termed STICS (STarvation Induced Cytoplasmic Structure). We propose that STICS formation might facilitate the switch from general translation to the specialized protein translation occurring during starvation. Together, our preliminary experiments uncovered a complex regulatory system that coordinates the necessary changes in the activity of translation, endocytosis and protein turnover in the MVB pathway to ensure survival under starvation conditions. The goal of the proposed research is to characterize this regulatory system and to determine how malfunction of this system affects cellular growth and adaptation.

Public Health Relevance

The proposed project studies how cellular metabolism regulates the function of a set of proteins, called ESCRTs, that are involved in protein turnover, cell division and formation of retroviruses. This knowledge has the potential to help us understand on a cellular level how nutrients might affect the pathology of human diseases such as HIV and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074171-07
Application #
8228067
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2006-03-05
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
7
Fiscal Year
2012
Total Cost
$336,369
Indirect Cost
$111,373
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Babst, Markus (2014) Quality control: quality control at the plasma membrane: one mechanism does not fit all. J Cell Biol 205:11-20
Mageswaran, Shrawan Kumar; Dixon, Megan Gorringe; Curtiss, Matt et al. (2014) Binding to any ESCRT can mediate ubiquitin-independent cargo sorting. Traffic 15:212-29
Shestakova, Anna; Curtiss, Matt; Davies, Brian A et al. (2013) The linker region plays a regulatory role in assembly and activity of the Vps4 AAA ATPase. J Biol Chem 288:26810-9
Babst, Markus; Odorizzi, Greg (2013) The balance of protein expression and degradation: an ESCRTs point of view. Curr Opin Cell Biol 25:489-94
Keener, Justin M; Babst, Markus (2013) Quality control and substrate-dependent downregulation of the nutrient transporter Fur4. Traffic 14:412-27
Hill, Christopher P; Babst, Markus (2012) Structure and function of the membrane deformation AAA ATPase Vps4. Biochim Biophys Acta 1823:172-81
Jones, Charles B; Ott, Elizabeth M; Keener, Justin M et al. (2012) Regulation of membrane protein degradation by starvation-response pathways. Traffic 13:468-82
Babst, Markus (2011) MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. Curr Opin Cell Biol 23:452-7
Babst, Markus; Davies, Brian A; Katzmann, David J (2011) Regulation of Vps4 during MVB sorting and cytokinesis. Traffic 12:1298-305
Shestakova, Anna; Hanono, Abraham; Drosner, Stacey et al. (2010) Assembly of the AAA ATPase Vps4 on ESCRT-III. Mol Biol Cell 21:1059-71

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