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Involvement of Inositol Pyrophosphates in Autophagy Regulation

by
Michael Po-Hao Chen
M.S., National Yang-Ming University
Taiwan - 2003


Thesis Advisor Shengkan Victor Jin, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

RWJMS Pharmacology Department
4th floor Conference Room R-400A
Piscataway

Tuesday, August 7, 2012
10:00 a.m.


Abstract

Inositol phosphates are implicated in the regulation of autophagy; however, the exact role of each inositol phosphate species is unclear. In this study, we systematically analyzed the highly conserved inositol polyphosphate synthesis pathway in S. cerevisiae for its role in regulating autophagy. Using yeast mutants that harbored a deletion in each of the genes within the inositol polyphosphate synthesis pathway, we found that deletion of KCS1, and to a lesser degree IPK2, led to defect in autophagy. KCS1 encodes an inositol hexakisphosphate/heptakisposphate kinase that synthesizes 5-IP7 and IP8; and IPK2 encodes an inositol polyphosphate multikinase required for synthesis of IP4 and IP5. We characterized the kcs1â┤ mutant strain in detail. The kcs1â┤ânyeast exhibited reduced autophagic flux, which might be caused by both the reduction in autophagosome number and autophagosome size as observed under nitrogen starvation. The autophagy defect in kcs1â┤ strain was associated with mislocalization of pre-autophagosomal structure (PAS) and a defect in Atg18p release from the vacuole membrane under nitrogen deprivation conditions. Interestingly, formation of autophagosome-like vesicles was commonly observed to originate from the plasma membrane in the kcs1â┤ strain. Our results indicate that lack of KCS1 interferes with proper localization of pre-autophagosomal structure (PAS), leads to reduction of autophagosome formation, and causes the formation of autophagosome-like structure in abnormal subcellular locations.


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