{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPRING (also known as C12ORF49) is a glycosylated, Golgi‐resident membrane protein that plays a pivotal role in regulating lipid homeostasis by modulating the sterol‐regulatory element binding protein (SREBP) pathway. In particular, SPRING is essential for the proper trafficking and function of the SREBP cleavage‐activating protein (SCAP), ensuring the efficient processing of the SREBP precursor. Loss of SPRING results in mislocalization of SCAP and diminished nuclear SREBP signaling, which impairs the transcriptional control of lipid biosynthesis genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have uncovered that SPRING functions as a crucial cofactor for site‐1 protease (S1P) maturation. By facilitating the conversion of S1P from its inactive precursors into its mature forms, SPRING supports the proteolytic activation of SREBP and other substrates that govern lipid metabolism and the unfolded protein response. This molecular mechanism underscores the broader impact of SPRING on maintaining cholesterol and lipid balance in cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther insights have emerged from genome‐wide genetic interaction screens in cells with disrupted de novo fatty acid synthesis. In these studies, SPRING—initially identified as an uncharacterized factor termed LUR1—was shown to regulate exogenous lipid uptake by modulating SREBF2 signaling during lipid starvation, thereby acting as a metabolic buffering agent when endogenous lipid production is compromised."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementary work has also demonstrated that SPRING’s role in lipid metabolism extends in vivo. Its interaction with the membrane‐bound transcription factor peptidase, site 1 (MBTPS1), is necessary for proper SREBP cleavage, and its depletion in zebrafish models leads to impaired dietary lipid clearance. Moreover, human studies have associated genetic variants in SPRING with hyperlipidaemia, further highlighting its critical function in cholesterol and fatty acid regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging evidence suggests a clinical dimension to SPRING’s function. Altered expression of SPRING has been linked to tumor growth and prognosis in colorectal cancer, indicating that its regulation of lipid metabolic pathways may also contribute to cancer biology and serve as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anke Loregger, Matthijs Raaben, Joppe Nieuwenhuis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-14811-1"}], "href": "https://doi.org/10.1038/s41467-020-14811-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32111832"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32111832"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jian Xiao, Yanni Xiong, Liu-Ting Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13238-020-00753-3"}], "href": "https://doi.org/10.1007/s13238-020-00753-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32666500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32666500"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Michael Aregger, Keith A Lawson, Maximillian Billmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Metab (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42255-020-0211-z"}], "href": "https://doi.org/10.1038/s42255-020-0211-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32694731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32694731"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Erol C Bayraktar, Konnor La, Kara Karpman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Metab (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42255-020-0206-9"}], "href": "https://doi.org/10.1038/s42255-020-0206-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32694732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32694732"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yiming Tao, Jia Luo, Hongyi Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chromosome 12 Open Reading Frame 49 Promotes Tumor Growth and Predicts Poor Prognosis in Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dig Dis Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10620-022-07751-x"}], "href": "https://doi.org/10.1007/s10620-022-07751-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36348128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36348128"}]}]}]}