The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The γ-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs' previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KIIα, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KIIα, or overexpression of a dominant-negative kinase-dead PI4KIIα mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KIIα or by restoring intracellular PI4P through "PI4P shuttling." Importantly, PI4KIIα's role in autophagy is distinct from that of PI4KIIIβ and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP 2 ) generation. Thus, GABARAPs recruit PI4KIIα to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KIIα and PI4P are essential effectors of the GABARAP interactome's fusion machinery.autophagy | GABARAP | PI4P | PI4KIIα | autophagosome:lysosome fusion
Background: Palmitoylation of phosphatidylinositol 4-kinase II␣ (PI4KII␣) regulates its function and Golgi localization, and cholesterol depletion delocalizes Golgi PI4KII␣ and inhibits activity. Results: Palmitoyl acyltransferases (PATs) that palmitoylate PI4KII␣ were identified. Cholesterol extraction inhibited PI4KII␣ association with PATs, decreased palmitoylation, and reduced Golgi phosphatidylinositol 4-phosphate. Conclusion: Cholesterol has a critical role in regulating PI4KII␣ interaction with PATs and palmitoylation. Significance: This study uncovered a novel mechanism for preferential recruitment of PI4KII␣ to Golgi.
Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2α subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.
A decrease in visfatin level was demonstrated in pre-eclampsia, suggesting that visfatin and adipokine-associated metabolic abnormalities are involved in the pathogenesis of the disease.
The study demonstrated elevated serum levels of adiponectin and leptin as well as a higher free leptin index in women with pre-eclampsia, suggesting these as important factors contributing to this complication of pregnancy.
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