Autophagy paradox and ceramide

Abstract

Sphingolipid molecules act as bioactive lipid messengers and exert their actions on the regulation of various cellular signaling pathways. Sphingolipids play essential roles in numerous cellular functions, including controlling cell inflammation, proliferation, death, migration, senescence, tumor metastasis and/or autophagy. Dysregulated sphingolipid metabolism has been also implicated in many human cancers. Macroatuophagy (referred to here as autophagy) “self-eating”, is characterized by nonselective sequestering of cytosolic materials by an isolation membrane, which can be either protective or lethal for cells. Ceramide (Cer), a central molecule of sphingolipid metabolism, has been extensively implicated in the control of autophagy. The increasing evidence suggests Cer is highly involved in mediating two opposing autophagic pathways, which regulate either cell survival or death, autophagy paradox. However, the underlying mechanism that regulates the autophagy paradox remains unclear. Therefore, this review focuses on recent studies with regard to the regulation of autophagy by Cer and elucidate the roles and mechanisms of action of Cer in controlling autophagy paradox.

Autophagy regulates sphingolipid levels in the liver

“…Although the exact means of how increased sphingolipid metobolism regulates autophagy is not well-understood, many studies have pointed to direct signaling by ceramide as a mechanism to stimulate autophagy (reviewed elsewhere) ( 17,53,(58)(59)(60). In particular, ceramide has been shown to induce autophagy via direct anchoring of autophagosomes to mitochondria ( 21 ), through downregulation consistent with the conclusion that excessive de novo sphingolipid synthesis drives autophagy-dependent triglyceride degradation.…”

“…Several studies have implicated the sphingolipid metabolic pathway in autophagy through direct addition of sphingolipids ( 21,52 ), the use of inhibitors of metabolism (either chemical or genetic) ( 24 ), and by indirect activation of de novo biosynthesis ( 17,25,53,54 ). In our study, we asked if initiation of de novo sphingolipid biosynthesis alone, in the absence of other stimuli, could directly activate autophagy in the liver, an organ where autophagy has been shown to be critical for maintaining normal homeostasis and preventing metabolic disease ( 38 ).…”

“…Ceramide undergoes anabolic reactions to generate sphingomyelin and various glycosphingolipids, or catabolic reactions, which lead to the generation of sphingosine and sphingosine-1-phosphate (S1P). Alterations in ceramide metabolism have been implicated in many pathophysiologies, including aging ( 4-6 ), neurodegeneration ( 7,8 ), metabolic diseases ( 9-15 ), cancer (16)(17)(18)(19)(20), and stress responses ( 5 ). However, the mechanisms that regulate cellular ceramide levels under physiologic and pathophysiologic conditions are still not well-understood.…”

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

“…Sphingolipids including ceramide, sphingosine, and S1P have been shown to stimulate macroautophagy (hereafter referred to as "autophagy") (36)(37)(38). As autophagy is a cell-autonomous defense mechanism against intracellular bacteria (39) and a relationship between autophagy and sphingosine metabolism is actively discussed in the field (40), we wondered whether LpSpl would modulate autophagy in human cells.…”

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells     

“…Follow-up analyses of this observation can be directed to the identification of host and viral targets for ubiquitin ligases and deubiquitinases, host adaptor proteins, or the role of virus-induced sphingolipids in tuning endosomophagy [34]. Notably, sphingolipids have key roles in the regulation of autophagy at the levels of transcription, translation, and morphogenesis of autophagosomes [62]. Another emerging question is how Gal3 and ubiquitin turnover are orchestrated on the ruptured membranes.…”