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. 

Investigating the role of neutral sphingomyelinases in membrane vesicle trafficking

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis.

Phosphoinositide turnover regulates multiple cellular processes. Compared with their well-known cytosolic roles, limited information is available on the functions of nuclear phosphoinositides. Here, we show that phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2) stably associates with electron-dense particles within the nucleus that resemble interchromatin granule clusters. These PtdIns(4,5)P2-containing structures have a distribution which is cell-cycle dependent and contain components of both the transcriptional and pre-mRNA processing machinery, including RNA polymerase II and the splicing factor SC-35. Immunodepletion and add-back experiments demonstrate that PtdIns(4,5)P2 and associated factors are necessary but not sufficient for pre-mRNA splicing in vitro, indicating a crucial role for PtdIns(4,5)P2-containing complexes in nuclear pre-mRNA processing.

Nuclear PtdIns(4,5)P-2 assembles in a mitotically-regulated particle involved in pre-mRNA splicing

Nuclear Lipids and Their Metabolic and Signaling Properties

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Nuclear Lipids and Their Metabolic and Signaling Properties