Sphingolipids and Inositol Phosphates Regulate the Tau Protein Phosphorylation Status in Humanized Yeast

Frontiers in Cell and Developmental Biology

Francisco Estruch¹  Lino Bojunga²  Jose A. Prieto²  Francisca Randez-Gil²  Joris Winderickx⁴  Maurizio Del Poeta⁵ 

[1] Departament of Biochemistry and Molecular Biology, Universitat de València, Valencia, Spain;Department of Biotechnology, Instituto de Agroquímica y Tecnología de los Alimentos, Consejo Superior de Investigaciones Científicas, Valencia, Spain;Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, United States;Functional Biology, KU Leuven, Leuven, Belgium;Veterans Administration Medical Center, Northport, NY, United States;

关键词: Saccharomyces cerevisiae;    1-IP7;    Pho85;    ceramide;    Sit4;    Ypk1;   

DOI  :  10.3389/fcell.2020.592159

来源: DOAJ

【 摘 要 】

Hyperphosphorylation of protein tau is a hallmark of Alzheimer’s disease (AD). Changes in energy and lipid metabolism have been correlated with the late onset of this neurological disorder. However, it is uncertain if metabolic dysregulation is a consequence of AD or one of the initiating factors of AD pathophysiology. Also, it is unclear whether variations in lipid metabolism regulate the phosphorylation state of tau. Here, we show that in humanized yeast, tau hyperphosphorylation is stimulated by glucose starvation in coincidence with the downregulation of Pho85, the yeast ortholog of CDK5. Changes in inositol phosphate (IP) signaling, which has a central role in energy metabolism, altered tau phosphorylation. Lack of inositol hexakisphosphate kinases Kcs1 and Vip1 (IP6 and IP7 kinases in mammals) increased tau hyperphosphorylation. Similar effects were found by mutation of IPK2 (inositol polyphosphate multikinase), or PLC1, the yeast phospholipase C gene. These effects may be explained by IP-mediated regulation of Pho85. Indeed, this appeared to be the case for plc1, ipk2, and kcs1. However, the effects of Vip1 on tau phosphorylation were independent of the presence of Pho85, suggesting additional mechanisms. Interestingly, kcs1 and vip1 strains, like pho85, displayed dysregulated sphingolipid (SL) metabolism. Moreover, genetic and pharmacological inhibition of SL biosynthesis stimulated the appearance of hyperphosphorylated forms of tau, while increased flux through the pathway reduced its abundance. Finally, we demonstrated that Sit4, the yeast ortholog of human PP2A protein phosphatase, is a downstream effector of SL signaling in mediating the tau phosphorylation state. Altogether, our results add new knowledge on the molecular effectors involved in tauopathies and identify new targets for pharmacological intervention.

【 授权许可】

Unknown