ATP8B2-mediated asymmetric distribution of plasmalogens regulates plasmalogen homeostasis and plays a role in intracellular signaling (Part 2)

Honsho M, Mawatari S, and Fujiki Y. (2022) ATP8B2-mediated asymmetric distribution of plasmalogens regulates plasmalogen homeostasis and plays a role in intracellular signaling. Frontiers in Molecular Biosciences

Our previous blog on this article summarized the work of Honsho et al where they demonstrated that a specific P4-ATPase, ATP8B2, is responsible for translocating plasmalogens, a unique class of lipid that contains a vinyl-ether bond at the sn-1 position, from the outer leaflet of the plasma membrane bilayer to the inner leaflet, causing the essential asymmetric distribution of plasmalogens. Also, they showed that the downregulation of ATP8B2 has a role in plasmalogen sensing and causes an upregulation of fatty acyl-CoA reductase 1 (FAR1) and an increase in plasmalogen levels. To further this work, Honsho et al looked at the role of the asymmetric distribution of plasmalogens on the phosphorylation of protein kinase B (AKT). AKT is a main regulator of cellular metabolism and its recruitment to the plasma membrane, which is essential for the phosphorylation of AKT and its activation, is impaired in plasmalogen deficiency. Because of this, they hypothesize that an asymmetric distribution of plasmalogens is associated with cellular metabolism.

To confirm the necessity of plasmalogens for the phosphorylation of AKT, they lowered the level of plasmalogens in HeLa cells and tested the phosphorylation state of AKT. They knocked down alkylglycerone-phosphate synthase (AGPS), an enzyme in the plasmalogen biosynthetic pathway, and confirmed that the AGPS protein was lowered by 60-70% in the cells and plasmalogen levels were lowered by 30%. Two domains of AKT were tested for phosphorylation, threonine 308 (T308) in the kinase domain and serine 473 (S473) in the C-terminal regulatory domain and both were found to be suppressed. These findings support the importance of plasmalogen level for phosphorylation of AKT.

Although it was confirmed that plasmalogen homeostasis is required for AKT phosphorylation, the authors also wanted to determine if the location of plasmalogens was important. To complete this, ATP8B2, a P4-ATPase responsible for translocating plasmalogens from the outer leaflet of the plasma membrane to the inner leaflet, was knocked down in the cells. Phosphorylation of T308 and S473 on AKT were measured and both were reduced. As discussed in our previous blog, when ATP8B2 is knocked down in HeLa cells the asymmetric distribution of plasmalogens in the membrane is compromised. Together these findings implicate ATP8B2-mediated localization of plasmalogens to the phosphorylation of AKT. 

Honsho et al were interested in the role of plasmalogens and their location in the activation of AKT. They demonstrated that when plasmalogens are reduced there is a similar decrease in phosphorylation of the protein kinase and that this is also dependent on an enrichment of plasmalogens in the inner leaflet of the membrane. Although in disorders with plasmalogen deficiency, such as Rhizomelic chondrodysplasia punctata, the inability to produce plasmalogens drives the pathology, the importance of the asymmetric distribution of plasmalogens may prove to be an important player or target in other diseases. Further work into plasmalogen homeostasis is needed to fully understand their role in such disorders.