Neutral sphingomyelinase 1 regulates cellular fitness at the level of ER stress and cell cycle

Neutral sphingomyelinase 1 (nSMase1) belongs to the sphingomyelinase enzyme family that hydrolyzes sphingomyelin to produce signaling active lipid ceramide and phosphorylcholine. The molecular characterization and biological function of nSMase1 remain poorly studied. Here, we report that nSMase1 (gene name: SMPD2) knockdown reduces LAMP1 at the mRNA levels and is required for initiating a full-potential unfolded protein response under ER stress. Additionally, SMPD2 KD dramatically reduces the global protein translation rate. We further show that SMPD2 KD cells are arrested in the G1 phase of the cell cycle and that two important cell cycle regulating processes - PI3K/Akt pathway and Wnt signaling pathway are altered. Taken together, we propose a role for nSMase1 in buffering ER stress and modulating cellular fitness via cell cycle regulation.