Purpose of review: Lipid metabolism and de-novo lipogenesis (DNL) is broadly controlled by the SREBP transcription factors. These transcription factors are matured from membrane-anchored precursor proteins by the proteolytic actions of the proteases S1P and S2P. In this review, we summarize the current understanding of SPRING, a recently identified activator of S1P.
Recent findings: Recent studies of SPRING using animal, cellular, biochemical, and biophysical methods have established SPRING as a core component of the SREBP machinery. Deletion of SPRING in cells and animal livers specifically reduces SREBP activity yet leaves other S1P substrates intact, demonstrating an SREBP-specific role for SPRING in licensing S1P activity. Mechanistic biochemical and structural studies revealed that SPRING activates S1P by competitively displacing its inhibitory pro-domain and elucidated how small molecule inhibition of S1P can be accomplished.
Summary: Current studies have shown how SPRING activates S1P and uncovered a critical role for SPRING in the SREBP pathway. Further studies are warranted to understand this emerging, connection between SPRING and the regulation of DNL through SREBP.
Keywords: C12ORF49; MBTPS1; SPRING; SREBP; cholesterol metabolism; proteases; scap; site-1-protease.
Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.