Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 54 (1), 5-19

Sphingolipids: Regulators of Crosstalk Between Apoptosis and Autophagy

Affiliations
Review

Sphingolipids: Regulators of Crosstalk Between Apoptosis and Autophagy

Megan M Young et al. J Lipid Res.

Abstract

Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to address how sphingolipids mediate the "switch" between the cell survival and cell death. As sphingolipid metabolism is frequently dysregulated in cancer, sphingolipid-modulating agents, or sphingomimetics, have emerged as a novel chemotherapeutic strategy. Ultimately, a greater understanding of sphingolipid-mediated crosstalk between apoptosis and autophagy may be critical for enhancing the chemotherapeutic efficacy of these agents.

Figures

Fig. 1.
Fig. 1.
A generalized overview of the regulation of apoptosis by sphingolipids. Sphingolipids have direct effects on mitochondrial function. Ceramide (Cer) assembles channels in the outer membrane of mitochondria to promote the release of cytochrome c (cyt c) for caspase-9 activation. Dihydroceramide (dHCer) inhibits ceramide channel formation. Similarly, the ganglioside GD3 permeabilizes mitochondria in a ROS and calcium-dependent manner. Additionally, Cer directly inhibits mitochondrial complex III to generate ROS. Cer promotes Bax activation and recruitment to the mitochondria through the PP2A-dependent dephosphorylation of Bax and formation of mitochondrial ceramide-rich macrodomains (MCRMs). Furthermore, mitochondrial Cer is metabolized to S1P and hexadecenal (hex), which directly activate Bax and Bak, respectively. i) Lysosomal effects. Cer directly binds and activates the lysosomal protease cathepsin D to enhance Bid cleavage and induction of the mitochondrial pathway of apoptosis. At low to moderate concentrations, sphingosine (Sph) becomes protonated and trapped within lysosomes, leading to lysosomal membrane permeabilization (LMP) and cleavage of Bid for the induction of apoptosis. ii) Bcl-2 family. Sph downregulates antiapoptotic Bcl-2 and Bcl-xL to promote apoptosis. Cer activates PP1 and PP2A to regulate the alternative splicing of apoptosis-promoting variants Bcl-xS and Caspase-9 and inhibit the antiapoptotic effects of Bcl-2, respectively. iii) Kinase signaling. Cer directly activates protein kinase C ζ (PKCζ), which mediates the activation of JNK and inhibition of Akt to promote apoptosis. S1P suppresses Cer-mediated activation of JNK and activates pro-survival Akt/mTORC1, MAPK/ERK, and NF-κB signaling pathways through cell surface receptors. Sph-induced apoptosis is characterized by suppression of MAPK/ERK signaling, while gangliosides enhance apoptosis through the inhibition of NF-κB.
Fig. 2.
Fig. 2.
A generalized overview of the regulation of autophagy by sphingolipids. Sphingolipids have direct effects on autophagy. Ceramide (Cer) activates calpain, which cleaves Atg5 to generate a protein fragment that promotes apoptosis and suppresses autophagy. Mitochondrial Cer mediates mitophagy (i.e., autophagic degradation of mitochondria) through the direct association of ceramide with LC3-II. Sphingosine (Sph) is likely to suppress autophagosome maturation. i) mTORC1 signaling. Cer suppresses Akt activation to relieve the downstream inhibitory effects of mTORC1 on autophagy. Similarly, the ganglioside-induced autophagy is associated with the suppression of Akt. Acid sphingomyelinase-derived Cer also shuts down mTORC1 activity during amino acid deprivation in a PP2A-dependent manner. Cer-induced autophagy is also associated with the downregulation of nutrient transporter proteins to activate autophagy through AMPK and lead to a bioenergetic crisis for the induction of cell death. S1P differentially regulates mTOR activity. Overexpression of SK1 as well as ligation of the cell surface receptor S1P5 inhibits mTORC1 to induce S1P-mediated autophagy. In contrast, ligation of S1P3 by S1P is reported to activate mTORC1 for the suppression of Cer-induced autophagy. ii) Transcriptional regulation. Cer-mediated inhibition of Akt activates FOXO3 to upregulate BNIP3 expression. BNIP3 liberates Beclin 1 for the induction of autophagy through the competitive binding of Bcl-2, Bcl-xL, and Mcl-1. Cer-mediated activation of JNK and the transcription factor, c-Jun, upregulates Beclin 1 and LC3 expression to promote autophagy. JNK activation also disrupts the inhibitory Beclin 1:Bcl-2 complex through direct phosphorylation of Bcl-2. The upregulation of Beclin 1 by Cer also is mediated by the activation of NF-κB. Additionally, ganglioside-induced autophagy is dependent on the production of ROS, which regulates Atg4 activity. iii). ER stress. The accumulation of Cer and S1P within the ER has been associated with the induction of ER stress leading to autophagy. Interestingly, S1P-mediated ER stress leads to the activation of Akt for cell survival. In contrast, Cer-mediated ER stress has been associated with inhibition of mTORC1 for autophagy induction as well as the upregulation of Atg5 and Beclin 1.

Similar articles

See all similar articles

Cited by 91 PubMed Central articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback