Table 1.
Summary of studies aiming to reveal correlations between endocytosis, intracellular transport, and cellular lipids. Upward arrows mark increased level of lipids, binding, or steps leading to toxicity, and downward arrows mark the opposite. The number of arrows indicate the size of the effects. Empty boxes mean not measured, and the sign for similar (~) means no or very minor changes. “Endo → Golgi” means transport from endosomes to the Golgi apparatus. “Golgi → ER” means transport from the Golgi apparatus to the endoplasmic reticulum.
| Treatment | Binding | Uptake 1 | Endo → Golgi | Golgi → ER | Toxicity | Cer | GlcCer LacCer |
Gb3 | Acyl PL | Ether PL | Other Information |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Fumonisin 2 | Stx ↓↓ | ~ | Stx ↓↓↓ | Stx ↓↓↓ | ↓↓ | ↓↓ | ↓↓ | PE ↑↑ | PE ↑↑ PC ↓ |
No effect on ricin | |
| PDMP 3 | Stx ↓↓ | ~ | Stx ↓↓↓ | Stx ↓↓ | ~ | ↓↓ | ↓↓ | ~ | ~ | No effect on ricin | |
| HG 4 | Stx ↓ | ~ | ~ | Stx ↓↓ | Stx ↓↓↓ | ~ (↑) | ↓↓ | ↓↓ | PI ↑↑ LPI ↑↑↑ |
PE ↑↑ PC ↑↑ |
No effect on ricin. See also 4 |
| Cell density 5 | Stx ↓↓ | ~ | ~ | ~ | Stx ↓↓ | ↑ | ↑ | ↑ | PA↑↑ PI + PE ↓ |
PE ↓ PC ↓ |
No effect on diphtheria toxin |
| 2-DG 6 | ~ | ~ | ~ | ~ | Stx ↓(↓) | ~ (↑) | Cont. 3% 2-DG | ↓ 1% 2-DG | Inhibits release of Shiga toxin A1 in ER | ||
| FDG 7 | Stx ↓ | ~ | ~ | Stx ↓ | Stx ↓↓↓ | ~ | ↓↓↓ | ↓↓↓ | PI ↑ | Inhibits GlcCer synth. | |
| Lyso PL 8 (LPI 18:0) |
Stx ↓↓ | Stx ↓↓↓ | Stx ↓↓↓ | PM lipid packing ↓ | |||||||
| Polyunsaturated FA 9 | Stx ↓ | Stx ↓ | Stx ↓ | Stx ↓↓↓ | Varying effect on other toxins (see 9) | ||||||
| OHOA 10 | ~ | ~ | Ricin ↑↑ | ~ | Ricin ↑↑ | ~ | ~ | ~ (see 11) | ~ (see 11) | PM lipid packing ↓ | |
| DAG kinase and PLD 11 | ~ | Ricin ↑↑ | ~ | Ricin ↑ | ~ | ~ | ~ (most) | ~ | See text for DAG, PA and PG |
1 In this column, the similar sign (~) means uptake changed similar to binding 2 Fumonisin B1: 10 µM, 48 h, HEp-2 cells [164]. 3 DL-threo-1-phenyl-2-decanoylamino-3morpholino-1-propanol: 1 µM, 24 h, HEp-2 cells [164]. 4 sn-1-O-hexadecylglycerol: 20 µM, 24 h, HEp-2 cells. No or only minor effect on cytotoxicity by ricin, cholera toxin, or diphtheria toxin. No effect on transferrin endocytosis. Toxicity also shown for Stx2 in HEp-2, HBMEC and HBMEC-2 cells [176,177]. 5 Data in table shown for HEp-2 cells grown for 1, 2, or 3 days to obtain a cell confluency of 20–30% on Day 1 and 80–90% on Day 3. Data given for changes due to increased cell density. Similar toxicity data were shown in HeLa cells. TLC analyses revealed less Gb3 at high density in HeLa cells and close to similar amounts in HEp-2 cells [33]. 6 2-Deoxy-D-glucose: 10 mM, 4 h and 24 h, HEp-2 cells. Several changes in the lipidome; 1–3% of GSLs contain 2-DG. Similar toxicity observed with Stx2 and diphtheria toxin, but no change in toxicity with ricin. 2-DG also protected HT-20 and SW480 cells against Shiga toxicity. 2-DG decreased transferrin endocytosis, but less than that of Shiga toxin [178]. 7 2-Fluoro-2-deoxy-D-glucose: 1 mM, 24 h, HEp-2 cells. FDG inhibits GlcCer synthase; effect on GSLs observed after 24 h, not after 4 h. Protection against Stx2 similar to protection against Shiga toxin in HEp-2 cells, but only a very weak protection against ricin and no protection against diphtheria toxin. Similar protection against Shiga toxin in MCF-7, HT-29, and HBMEC cells [179]. 8 Lyso PL: Data are shown for many different lyso PLs, 5–20 µM, 30 min, Hep-2 cells. Largest effects observed with the most conical lyso PL, i.e., those with the largest head groups (e.g., LPI 18:0 with a large head group: LPI > LPS > LPC >LPE > LPA). Symbols in the table are showing changes with LPI 18:0. The effects were reversed by the addition of methyl-β-cyclodextrin. Similar effects observed with Stx2 [180]. In a follow-up article, these lyso PLs were shown to perturb clathrin-mediated endocytosis, with the largest effects observed with the lipids with the largest head groups [181]. 9 Polyunsaturated FA: 50 µM EPA (20:5) or DHA (22:6), 2 days, HEp-2 cells. Similar reduced toxicity observed with cholera toxin, whereas a slightly increased toxicity was observed with ricin. Only minor decrease in transferrin endocytosis [182]. 10 2-Hydroxyoleic acid (Minerval®): 12 µM, 3 h, HeLa cells. OHOA incorporated into ~11% of acylated PL and 10% of ether lipids. A similar toxicity was observed in HEp-2 and U2-OS cells [171]. 11 DAG kinase and PLD (phospholipase D): Use of inhibitors and siRNA to modify the levels of DAG and PA in HEp-2 cells. Inhibitors led to increased transport to Golgi and increased endosome size and tubulation. Effect increased by combining the inhibitors. No changes in recycling or degradation of ricin [183]. See the main text for further details.