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SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P.
Sebastian Hendrix1, Josephine M E Tan1, Klevis Ndoj1
1Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands.
Molecular and Cellular Biology
|May 15, 2024
Summary
SPRING protein facilitates the maturation and activation of SREBP (sterol regulatory element-binding protein) transcription factors by interacting with site-1-protease (S1P). This interaction is crucial for lipid metabolism regulation.
Area of Science:
- Molecular Biology
- Cellular Metabolism
- Lipid Metabolism Regulation
Background:
- Sterol regulatory element-binding proteins (SREBPs) are key regulators of lipid metabolism.
- SREBP activation involves translocation to the Golgi and cleavage by site-1-protease (S1P).
- S1P itself requires autocatalytic cleavage for maturation.
Purpose of the Study:
- To investigate the role of SPRING (C12ORF29) in the S1P-mediated activation of SREBPs.
- To elucidate the interaction between SPRING and S1P and its functional consequences.
Main Methods:
- Protein interaction studies (ectodomain interaction).
- Analysis of S1P autocatalytic cleavage and SREBP signaling in SPRING knockout cells and liver-specific knockout mice.
- Expression of SPRING variants and assessment of S1P maturation and substrate signaling.
Main Results:
- SPRING interacts with S1P, facilitating its autocatalytic cleavage into the mature S1PC form.
- SPRING's ectodomain supports S1P maturation and SREBP signaling, but S1P-mediated SPRING cleavage is not essential for these.
- Absence of SPRING impairs S1P maturation and Golgi trafficking, leading to severely attenuated SREBP signaling, while ATF6 signaling remains unaffected.
Conclusions:
- SPRING acts as a dedicated licensing factor for SREBP-specific activation by S1P.
- The interaction is critical for efficient SREBP pathway activation in lipid metabolism.
- SPRING's role is specific to SREBP activation, distinct from other S1P substrates like ATF6.
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