SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P

SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1P to mature S1P form. Here...

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Vydáno v:Molecular and cellular biology Ročník 44; číslo 4; s. 123 - 137
Hlavní autoři: Hendrix, Sebastian, Tan, Josephine M. E., Ndoj, Klevis, Kingma, Jenina, Valiloo, Masoud, Zijlstra, Lobke F., Ottenhoff, Roelof, Seidah, Nabil G., Loregger, Anke, Kober, Daniel L., Zelcer, Noam
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Taylor & Francis 2024
Témata:
Animals
Cell Biology
Endoplasmic Reticulum - metabolism
Golgi Apparatus - metabolism
HEK293 Cells
Humans
Liver - metabolism
Mice
Mice, Knockout
Proprotein Convertases - genetics
Proprotein Convertases - metabolism
Proteolysis
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Signal Transduction
Sterol Regulatory Element Binding Proteins - genetics
Sterol Regulatory Element Binding Proteins - metabolism
SPRING
S1P
SREBP
proteolytic enzyme
C12ORF49
cholesterol regulation
post-transcriptional regulation
lipid metabolism
Cholesterol metabolism
proteolysis
ISSN:1098-5549, 0270-7306, 1098-5549
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Shrnutí:SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1P to mature S1P form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1P into its mature S1P form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRING cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1P and trafficking of S1P to the Golgi. However, despite reaching the Golgi in SPRING cells, S1P fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRING cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.
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Current affiliation: Institute for Diabetes, Obesity & Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 USA
Current affiliation: Myllia Biotechnology GmbH, Am Kanal 27, 1110 Vienna, Austria
Supplemental data for this article can be accessed online at https://doi.org/10.1080/10985549.2024.2348711.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1080/10985549.2024.2348711