NEK2A regulates PLIN2 expression through a SERBP1 dependent pathway

Lipid droplets are key organelles in lipid metabolism, and expression of the lipid droplet protein PLIN2 is tightly regulated. Here, we identify serine/threonine kinase NEK2A as a negative regulator of PLIN2 expression in human hepatoma cells. NEK2A depletion increased PLIN2 protein and mRNA levels, whereas its overexpression suppressed both. NEK2A contains two domains, a kinase domain and a coiled-coil domain. Notably, both the kinase-dead mutant and the truncated kinase domain suppressed PLIN2 expression, indicating that this regulation depends on the kinase domain but not its catalytic activity. Proteomic analysis identified SERBP1 as a NEK2A-binding partner required for this regulation. SERBP1 depletion abrogated NEK2A-mediated PLIN2 suppression, and the increase in PLIN2 expression was reversed by a PPARγ inhibitor. These findings define a kinase-independent NEK2A-SERBP1 pathway that regulates PLIN2 expression without altering triacylglycerol levels and provide insight into lipid droplet protein regulation beyond lipid storage.