TY - JOUR
T1 - A new SPRING in lipid metabolism
AU - Hendrix, Sebastian
AU - Zelcer, Noam
N1 - Funding Information: N.Z. is an established investigator of the Dutch Heart Foundation (2013T111) and is supported by a Vici grant from the Netherlands Organization for Scientific Research (NWO; 016.176.643). Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - PURPOSE OF REVIEW: The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism. RECENT FINDINGS: Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans. SUMMARY: Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.
AB - PURPOSE OF REVIEW: The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism. RECENT FINDINGS: Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans. SUMMARY: Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.
KW - C12ORF49
KW - MBTPS1
KW - S1P
KW - SPRING
KW - cholesterol metabolism
KW - posttranscriptional regulation
KW - sterol-responsive element binding protein
UR - http://www.scopus.com/inward/record.url?scp=85170582342&partnerID=8YFLogxK
U2 - https://doi.org/10.1097/MOL.0000000000000894
DO - https://doi.org/10.1097/MOL.0000000000000894
M3 - Review article
C2 - 37548386
SN - 0957-9672
VL - 34
SP - 201
EP - 207
JO - Current opinion in lipidology
JF - Current opinion in lipidology
IS - 5
ER -