Indiana University-Purdue University Indianapolis (IUPUI) / Key regulatory decisions of protein synthesis and autophagy are controlled by
the lysosomal nutrient sensing complex (LYNUS). To engage protein synthesis
signaling, LYNUS requires cellular availability of amino acids, adenosine
triphosphate (ATP), growth factors, and docking at the lysosomal membrane.
The molecular determinants of LYNUS signaling and docking are not completely
elucidated and may involve regulators of the lipid membrane structure and
function of the lysosome. Since ceramides are both bioactive second
messengers and determinants of lipid membrane stiffness, we investigated the
role of the ceramide-producing lysosomal acid sphingomyelinase (ASM) in the
homeostatic function of mammalian target of rapamycin (mTOR) signaling and
autophagy. Using ASM inhibition with either imipramine or siRNA against
SMPD1, in primary human lung cells or Smpd1+/- mice, we demonstrated that
ASM is an endogenous inhibitor of autophagy. ASM was necessary for
physiological mTOR signaling and maintenance of sphingosine levels. Whereas
overstimulation of ASM has been shown to trigger autophagy with impaired flux,
inhibition of ASM activity during homeostatic, non-stressed conditions triggered
autophagy with degradative potential, associated with enhanced transcription
factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis
genes, translocation to the nucleus and decreased sphingosine levels. These
findings suggest LYNUS signaling and autophagy are partially regulated by ASM.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/12536 |
| Date | 19 January 2016 |
| Creators | Justice, Matthew Jose |
| Contributors | Petrache, Irina, Roach, Peter J., Dong, X. Charlie, Yin, Xiao-Ming |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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