A new SPRING in lipid metabolism Blooming of a novel post-transciptional SREBP regulator

Cholesterol and fatty acids (FA) are vital for cellular integrity, serving as key components in cell structure, signaling, and metabolism. Dysregulation of cholesterol and FA homeostasis is associated with many pathologies, including cardiovascular diseases, neuropathies, and cancer. Consequently, cholesterol and FA levels require strict regulation. Sterol regulatory element-binding proteins (SREBPs) are the master regulators of cholesterol and FA homeostasis, and due to their central role in lipid metabolism, they are tightly controlled by a complex regulatory network.
This thesis investigates the identification and characterization of SPRING (SREBP Pathway Regulator in Golgi), a novel post-transcriptional regulator of the SREBP pathway. SPRING was discovered through unbiased genetic screening approaches aimed at identifying new determinants of lipid metabolism. SPRING is a glycosylated, Golgi-resident membrane protein that interacts with site-1 protease (S1P), an enzyme that processes SREBPs. It promotes the autocatalytic maturation of S1P into its enzymatically active form. Interestingly, while SPRING is essential for S1P-mediated SREBP activation, it is not required for S1P-dependant activation of ATF6, indicating its specificity within the SREBP pathway.
Structural analysis via cryo-electron microscopy reveals that SPRING supports S1P maturation by displacing the inhibitory pro-domain of S1P. In vivo studies in mice lacking hepatic Spring expression show diminished SREBP signaling, reduced cholesterol and FA synthesis, and protection from diet-induced liver fat accumulation. Furthermore, genome-wide association studies link genetic variations in SPRING to human lipid parameters, underscoring its physiological significance.
Overall, the thesis identifies SPRING as a core component of the SREBP machinery, advancing our understanding of cholesterol and FA homeostasis and offering potential therapeutic avenues for lipid-related diseases.