PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation

By Ashley M. Mackey, Deborah A. Sarkes, Ian A. Bettencourt, J. Asara, L. Rameh. 2014

41 citations recorded by the source corpus.

A feedback loop involving PIP4kγ and mTORC1 maintains basal mTORC1 activity under nutrient-deprived conditions. Maintaining a Basal Level of Activity Nutrients such as glucose and amino acids activate mammalian target of rapamycin complex 1 (mTORC1), a complex consisting of the kinase mTOR, which couples metabolic signals to pathways that trigger cellular proliferation and growth. When nutrients are limiting, mTORC1 activity is normally suppressed. Mackey et al. found that under nutrient-depleted conditions, the kinase PIP4kγ interacted with and activated mTORC1, which stimulated mTOR kinase activity at low levels. Under nutrient-replete conditions, mTOR phosphorylated PIP4kγ, inhibiting this pathway. Thus, PIP4kγ and mTORC1 exist in a feedback loop that ensures basal activity of mTORC1 during starvation and that is shut down when nutrients become available again. Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases that specifically use phosphatidylinositol 5-monophosphate (PI-5-P) as a substrate to synthesize phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Suppression of PIP4k function in Drosophila results in smaller cells and reduced target of rapamycin complex 1 (TORC1) signaling. We showed that the γ isoform of PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kγ reduced cell mass in cells in which mTORC1 is constitutively activated by Tsc2 deficiency. In Tsc2 null cells, mTORC1 activation was partially independent of amino acids or glucose and glutamine. PIP4kγ knockdown inhibited the nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced basal mTORC1 signaling in wild-type cells. PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. Furthermore, basal mTORC1 signaling was enhanced by overexpression of unphosphorylated wild-type PIP4kγ or a phosphorylation-defective mutant and decreased by overexpression of a phosphorylation-mimetic mutant. Together, these results demonstrate that PIP4kγ and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly regulated mTORC1 activation during starvation.

Subfields: Molecular Biology

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Citations in the corpus

PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism (2018, background): “There is also evidence for pools of PIP4K2A/PIP4K2B/PIP4K2C in the plasma membrane, Golgi, and nucleus, so the PIP4K enzymes are likely to havemany other functions beyond autophagy regulation (Bultsma et al., 2010; Jones et al., 2006; Mackey et al., 2014).”
Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system (2016, background): “argued that PI5P4Kγ was negatively regulated by mTORC1 through direct phosphorylation at serine 324 and serine 328 (6).”
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “However, in line with our current findings, previous studies observed that knock-down of PIP4Kg resulted in an increase in autophagy (Mackey et al., 2014; Vicinanza et al., 2015), and a reduction of EGFP-HttQ74 aggregates in MEFs that was dependent on the presence of the autophagy gene, ATG7 (Mackey”