| dc.contributor.advisor | Groß, Julia Prof. Dr. | |
| dc.contributor.author | Choezom, Dolma | |
| dc.date.accessioned | 2022-07-21T11:39:26Z | |
| dc.date.available | 2022-07-28T00:50:10Z | |
| dc.date.issued | 2022-07-21 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14173 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9238 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Investigating the role of neutral sphingomyelinases in membrane vesicle trafficking | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Meinecke, Michael Prof. Dr. | |
| dc.date.examination | 2022-04-26 | de |
| dc.description.abstracteng | Evidence collected over the years has established small extracellular vesicle (sEV) or
exosome secretion as a novel paradigm for intercellular communication under both
physiological and pathological conditions. SEVs are generated as intraluminal vesicles
(ILVs) during multivesicular body (MVB) maturation in the endocytic pathway. Upon fusion
of MVBs with the plasma membrane, ILVs are released into the extracellular space as
sEVs. The molecular mechanisms that underlies ILV generation and the subsequent
sorting of these secretory MVBs from the conventional degradative MVBs remain largely
unraveled.
Neutral sphingomyelinase 2 (nSMase2, encoded by SMPD3) activity drives intraluminal
vesicle (ILV) generation for sEV secretion. In addition to its role in producing ceramide
required for membrane invagination to form ILVs, here, we report that nSMase2 regulates
sEV secretion through modulation of vacuolar H+
-ATPase (V-ATPase) activity.
Specifically, we show that nSMase2 inhibition induces V-ATPase complex assembly that
drives MVB lumen acidification and consequently reduces sEV secretion. Conversely, we
demonstrate that stimulating nSMase2 activity with the inflammatory cytokine TNFα
decreases acidification and increases sEV secretion. Thus, we unravel that nSMase2
activity affects MVB membrane lipid composition to counteract V-ATPase-mediated
endosome acidification, and thereby shift MVB fate towards sEV secretion.
The second part of this thesis focuses on neutral sphingomyelinase 1 (nSMase1,
encoded by SMPD2), which also belongs to the sphingomyelinase enzyme family. The
molecular characterization and biological function of nSMase1 remain poorly studied.
Here, we show that SMPD2 knockdown (KD) reduces LAMP1 at the mRNA levels and is
required for initiating a full-potential unfolded protein response under ER stress.
Additionally, SMPD2 KD dramatically reduces the global protein translation rate. We
further show that SMPD2 KD cells are arrested in the G1 phase of the cell cycle and that
two important cell cycle regulating processes - PI3K/Akt pathway and Wnt signaling
pathway are altered. Taken together, we propose a role for nSMase1 in buffering ER
stress and modulating cellular fitness via cell cycle regulation. | de |
| dc.contributor.coReferee | Enderlein, Jörg Prof. Dr. | |
| dc.subject.eng | SMPD2 | de |
| dc.subject.eng | SMPD3 | de |
| dc.subject.eng | lipids | de |
| dc.subject.eng | Cell Cycle | de |
| dc.subject.eng | Wnt Signaling | de |
| dc.subject.eng | Extracellular Vesicles | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14173-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Medizin (PPN619874732) | de |
| dc.subject.gokfull | Molecular medicine | de |
| dc.description.embargoed | 2022-07-28 | de |
| dc.identifier.ppn | 1811436714 | |
| dc.notes.confirmationsent | Confirmation sent 2022-07-21T11:45:01 | de |