Phosphoinositide acyltransferases: Greasing the Signal Transduction and Trafficking Machinery

Phosphoinositide (PIP) lipids are at the centre of molecular networks that control signal transduction, subcellular organization, and metabolic activity. Based on the phosphorylation pattern of the inositol headgroup, there are seven PIP species such as PI(4,5)P2 and PIP3. Each bind to a different set of cognate proteins, enabling their function. For example, PIP3 binds and activates the kinase Akt during growth factor signalling. Yet, there is a facet of PIP biology that is often overlooked: the acyl groups of PIPs. Interestingly, 50-70% of PIPs (and its parent lipid, phosphatidylinositol) specifically contain stearate (C18:0) at the sn-1 and arachidonate (C20:4) at the sn-2. This acyl enrichment is distinct from other phospholipids suggesting that the type of acyl chains matters towards PIP function. Moreover, the acyl profile of PIPs is subject to environmental conditions and genetics, including tumours. So, does it matter what kind of acyl chain one uses in PIPs Does the acyl composition of PIPs lead to functionality distinct pools of PIPs? And how is the acyl specificity of PIPs achieved? None of these questions and processes are well understood. The acyl profile of PIPs seems to be established by the acyltransferases LCLAT1 and MBOAT7 through acyl remodelling pathway. Yet again, these acyltransferases are poorly understood. We previously found that LCLAT1 silencing disturbed endocytosis and endosomal trafficking, and predominantly affected the parent PI and PI(4,5)P2 (Bone et al., Mol. Biol. Cell, 2017), suggesting that LCLAT1 may act on specific pools of PIPs. Now, we reveal that LCLAT1 also affects growth factor signalling, PI3K-PIP3-Akt signalling, cell proliferation and migration. Moreover, we suspect that LCLAT1 remodels specific pools of PIPs through localized domains. Overall, the acyl profile of PIPs and the enzymes that regulate this process are clearly important for cell function, yet much remains to be understood about both.