The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non‐vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT‐I). Inhibition of ceramide biosynthesis reduces CERT‐Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT‐dependent pathway.
The
first total synthesis of the potent antibiotic berkeleylactone
A is described in 10 steps with an overall yield of 9.5%. A key step
of our concise route is a late-stage, highly diastereoselective, sulfa-Michael
addition. The 16-membered macrocyclic lactone was formed via ring
closing metathesis and subsequent chemoselective reduction. The absolute
stereochemical configuration was confirmed by single-crystal X-ray
analysis. Synthetic berkeleylactone A was tested against several methicillin-resistant Staphylococcus aureus strains, and its potent antibacterial
activity was verified.
A general photocatalytic reductive strategy for the construction of unsymmetrical α-tertiary dialkyl ethers is reported. By merging Lewis acid-mediated ketal activation and visible-light photocatalytic reduction, in situ generated α-alkoxy radicals can engage in addition reactions with a variety of olefinic partners. Good reaction efficiency is demonstrated with a range of ketals of aromatic and aliphatic ketones. Extension to acetal substrates is also described, demonstrating the overall synthetic utility of this methodology for complex ether synthesis.
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