Fig. 8: A model for NEK1-regulated retromers that control the cell surface presence of membrane receptors, mitochondrial metabolism and RIPK1-mediated cell death and inflammation.

Phosphorylation of S302/S304 VPS26B by NEK1 modulates the recycling of SNX27-retromer and SNX2-retromer that deliver proteins from endosomes to cell surface membrane and lysosomes. NEK1 deficiency blocks the recycling of SNX27-retromer from cell surface to endosomes. Since SNX27-retromer is important for delivering GLUT1 to the cell surface membrane, NEK1 deficiency leads to reduced GLUT1 levels at the cell surface membrane which reduces glucose uptake. Reduced glucose uptake disrupts mitochondrial metabolism and reduces cellular levels of acetyl-CoA. Reduced acetyl-CoA inhibits the acetylation of A20 which promotes its lysosomal degradation. Reduced levels of A20 sensitizes to the activation of RIPK1-dependent cell death and inflammation which can be inhibited by Nec-1s and also by ketogenic diet which provides alternate source of acetyl-CoA to restore cellular levels of A20.