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Cited by 9Sphingolipid Metabolism and SignalingLipid metabolism and biosynthesisCancer, Lipids, and Metabolism

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; none of the 31 sources its claims cite is checked for support yet.

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

Open access
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·2024·Molecular and Cellular Biology
DOI 10.1080/10985549.2024.2348711PMC PMC11110692
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Abstract

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 S1PA to mature S1PC form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1PA into its mature S1PC 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 Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRINGKO 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 S1PA→C and trafficking of S1PC to the Golgi. However, despite reaching the Golgi in SPRINGKO cells, S1PC fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRINGKO 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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

SPRING interacts with S1P through their ectodomains and promotes S1P autocatalytic maturation, but its key role is as a dedicated licensing factor for SREBP-specific activation by S1P. Loss of SPRING severely blunts SREBP signaling while ATF6 signaling remains intact.

Key findings

  • SPRING and S1P co-immunoprecipitate via their ectodomains; SPRING co-expression increases the S1P C/S1P B ratio (Figure 1F, N = 4) and S1P cleaves SPRING at a predicted R45XLZ48 motif, releasing the SPRING ectodomain. Cleavage is blocked by the S1P inhibitor PF429242 or by SPRING mutations R45E or R43E,R45E,L47E,L48E.
  • The SPRING ectodomain (residues 49–205) restores sterol-dependent SREBP target genes (LDLR, SQLE, HMGCR, FDFT1, FASN) in Hap1 SPRING KO cells to the same degree as wild-type SPRING, whereas SPRING stump (1–48) does not. Cleavage-resistant SPRING mutants also restore SREBP signaling, indicating SPRING cleavage by S1P is not required for this function.
  • In SPRING KO cells, mature S1P C is still produced but modestly reduced (significant decrease in S1P C/S1P B ratio; minimal decrease in Golgi residency), and overexpressed S1P does not rescue SREBP signaling. In contrast, tunicamycin-induced ATF6 activation is unaffected in Hap1 SPRING KO cells and in livers of liver-specific Spring knockout (LKO) mice.
  • In LKO mice, AAV-mSpring reversed impaired hepatic SREBP signaling and low plasma cholesterol, and a cleaved mSPRING fragment was detected in plasma (N = 4 mice/group).

Methods

  • Cell models included HEK293T, HeLa, HepG2, Hap1 control/SPRING KO, and immortalized mouse Spring WT/KO fibroblasts. Cells were transiently transfected or stably transduced with SPRING variants and S1P constructs, sterol-depleted with lipoprotein-deficient serum plus mevalonate and simvastatin, and treated with PF429242 or tunicamycin.
  • Mouse experiments used liver-specific Spring KO (LKO; AlbCre Spring fl/fl) mice. AAV8-LP1-mSpring or AAV8-LP1-GFP was injected at 1 × 10^11 viral particles/kg into 13–18 week old male LKO mice (4/group), with sacrifice 2 weeks later; tunicamycin (1 mg/kg) was injected intraperitoneally into 8–11 week old male control and LKO mice (N = 6/group) for 8 h.
  • Main analyses were co-immunoprecipitation, immunoblotting, qPCR, plasma cholesterol measurement, and immunofluorescence colocalization of S1P-mCherry with Golgin97; statistics used ANOVA, t tests, or nonparametric alternatives with P < 0.05.

Limitations

  • The paper states that reliance on stable overexpression of SPRING cleavage mutants may override stoichiometric requirements and obscure subtle effects; future studies using endogenously produced mutant SPRING are needed.
  • The paper states that understanding of SPRING in lipid metabolism is largely limited to cell models, and that global SPRING ablation causes embryonic lethality; conditional models are needed for tissue-specific physiological roles.
  • Evident from the text: commercial anti-S1P and anti-SPRING antibodies did not detect endogenous proteins, so mRNA expression was used for some comparisons, and many mechanistic conclusions rely on epitope-tagged overexpressed constructs.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/10985549.2024.2348711

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 31 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Nonconventional S1P A to S1P C processing is not supported by SPRING.

    “and that nonconventional S1P A to S1P C is not supported by SPRING.”
    Quote in the paperSubstantial claim
  • Findingown data

    Abundance of stably expressed wild-type SPRING-Myc protein is increased in cells treated with S1P inhibitor PF429242.

    “abundance of stably expressed wild-type SPRING-Myc protein was also increased in cells treated with the specific S1P inhibitor PF429242 (Supplementary Figure 5B).”
    Quote in the paperNot a substantial claim
  • Findingown data

    SPRING expression is unchanged when S1P activity is inhibited by PF429242.

    “Reciprocally, SPRING expression was unchanged when S1P activity was inhibited by the high-affinity inhibitor PF429242 (Supplementary Figure 1D).”
    Quote in the paperSubstantial claim
  • Findingown data

    An intact B0/B site is required for cleavage and secretion of SPRING to the medium.

    “Similarly, an intact B 0 /B site is required for cleavage and secretion of SPRING to the medium (compare lanes 7 and 9).”
    Quote in the paperSubstantial claim
  • Findingown data

    Absence of SPRING modestly diminishes trafficking of S1P C to the Golgi.

    “and trafficking of S1P C to the Golgi.”
    • Also stated in: § Results · plain
      “absence of SPRING resulted in a minimal, albeit significant, decrease in Golgi residency of S1P”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one. 22
  • The quote only partly states this claim. 2
  • Probably not a substantial claim. 12

  • It may state two separate claims as one.

    Findingown data

    ATF6 signaling is unaffected in SPRING KO cells and LKO mice.

    “that of ATF6, another S1P substrate, was unaffected in these models.”
    • Also stated in: § Results · plain
      “the ATF6-regulated transcriptional response (i.e., expression of ATF6, DDIT3, HSPA5, ATF4, and XBP1) to tunicamycin was indistinguishable from that of wildtype controls.”
    • Also stated in: § Results · plain
      “tunicamycin increased the expression of hepatic ATF6 targets in vivo to the same extent in wild-type control and LKO mice (Figure 6C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic transduction with AAV-mSpring fully reverses impaired hepatic SREBP-signaling and reduced plasma cholesterol in LKO mice.

    “This phenotype was fully reversed by hepatic transduction with AAV-mSpring, but not with the control AAV-GFP (Figure 3B and C).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    S1P-mediated cleavage of SPRING leads to secretion of the SPRING ectodomain in liver-specific Spring knockout mice transduced with AAV-mSpring.

    “and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring.”
    • Also stated in: § Results · plain
      “a cleaved mSPRING fragment was readily detected by immunoblotting in plasma of AAV-mSpring transduced mice”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Expression of S1P (MBTPS1) is unchanged in cells lacking SPRING and in livers from LKO mice.

    “Expression of S1P (encoded by MBTPS1) was unchanged in cells lacking SPRING and in livers from LKO mice (Supplementary Figure 1B and C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Enhancement of proteolytic maturation by SPRING is specific for S1P and does not occur for FURIN and PCSK9.

    “Importantly, enhancement of proteolytic maturation was specific for S1P (also known as SKI-I or PCSK8), as absence or presence of SPRING did not change maturation of FURIN (PCSK3) and PCSK9”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    SREBP signaling is severely attenuated in SPRING KO cells and LKO mice.

    “whereas SREBP signaling was severely attenuated in SPRING KO cells and LKO mice”
    • Also stated in: § Results · plain
      “absence of SPRING attenuated sterol-dependent induction of the SREBP target genes LDLR, SQLE, HMGCR, FDFT1, and FASN (Figure 4A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Overexpression of S1P without concurrent rescue of SPRING fails to restore SREBP signaling, even though mature S1P C is readily detected.

    “In contrast, overexpression of S1P without concurrent rescue of SPRING failed to restore SREBP signaling, even though mature S1P C was readily detected (Figure 5C, lane 5 and 6).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Introduction of SPRING (R43E,R45E,L47E,L48E) into independent mouse fibroblast SPRING KO clones restores SREBP signaling similarly.

    “A similar result was obtained when introducing SPRING (R43E,R45E,L47E,L48E) into independent mouse fibroblast SPRING KO clones (Figure 4E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The S1P cleavage site in SPRING is at the end of an alpha-helical strand preceding the luminal cysteine-rich domain, a position common to other S1P substrates.

    “Analysis of the predicted Alphafold model positions the S1P cleavage-site in SPRING at the end of an a-helical strand, pre- ceding the luminal cysteine-rich domain, a position common to other S1P substrates (Supplementary Figure 3B).36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    SPRING is unable to stimulate activation of the S1P(D141-186) deletion mutant, and this mutant does not support SPRING cleavage and secretion.

    “We found that SPRING is unable to stimulate activation of this deletion mutant, and reciprocally, this mutant does not support SPRING cleavage and subsequent secretion to the medium (Figure 2D, lanes 6 and 10).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    SPRING absence abrogates SREBP signaling as reflected by impaired cholesterol and fatty acid synthesis in mammalian cells and LKO mice.

    “Accordingly, SPRING absence abrogates SREBP signaling as is functionally reflected by impaired cholesterol and fatty acid synthesis in mammalian cells and in liver-specific Spring KO mice (LKO).27,33”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    SPRING and S1P promote reciprocal proteolytic processing.

    “SPRING and S1P interact and promote reciprocal proteolytic processing.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Absence of SPRING decreases abundance of SREBP and severely attenuates proteolytic maturation of SREBP1 and SREBP2 from precursor to nuclear form.

    “Mechanistically, absence of SPRING decreases abundance of SREBP and severely attenuates the proteolytic maturation of SREBP1 and SREBP2 from their precursor, ER-resident form, to the transcriptionally competent nuclear form (Figure 1C and Supplementary Figure 1A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Absence of SPRING modestly decreases proteolytic activation of S1P, but this cannot account for the strong defect in SREBP signaling.

    “These experiments suggest that while absence of SPRING modestly decreases proteolytic activation of S1P, this cannot account for the strong defect in SREBP signaling.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    SPRING is not required for all S1P-dependent pathways but instead enables a specific pool of S1P to cleave SREBPs.

    “The most important contribution of the current study is to demonstrate that endogenous SPRING is not required for all S1P-dependent pathways but instead enables a specific pool of S1P to cleave SREBPs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Tunicamycin inhibits glycosylation and induces ER stress in an ATF6-dependent manner.

    “Tunicamycin inhibits glycosylation and as a consequence induces ER-stress in an ATF6-dependent manner.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Correctness of all constructs used in this study was confirmed by digestion analysis and sequencing.

    “Correctness of all constructs used in this study was confirmed by digestion analysis and sequencing (Supplementary Table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Cleavage at the B0/B site of S1P is performed in the ER in cis, and cleavage at the C0/C site occurs in the Golgi.

    “Cleavage at the B 0 /B site is performed in the ER in cis.The partially cleaved intermediate traffics to the Golgi where autocatalytic cleavage of the C 0 /C site occurs”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Study design and conductown data

    An equal amount of protein was loaded for analysis.

    “The protein concentration of the cleared lysates was determined using a BCA assay (ThermoFisher) following the manufacturer's protocol, and an equal amount was loaded for analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Gene expression was normalized to the expression of 36B4 and GAPDH.

    “Gene expression was normalized to the expression of 36B4 and GAPDH.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    SPRING is required for maintaining SCAP levels and localization in cells.

    “We previously reported that SPRING is required for maintaining SCAP levels and localization in cells.27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Immunoblots shown are representative of at least three independent experiments with similar results.

    “Unless indicated, immunoblots shown are representative of at least three independent experiments with similar results.”
    • Also stated in: § Statistics · plain
      “All immunoblots are representative of at least three independent experiments and box plots show the median (middle line), 25th, 75th percentile (box) and minimum and maximum values (whiskers).”
    • Also stated in: § Statistics · plain
      “All immunoblots are representative of at least three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Multiple independent clones were isolated and Spring expression and function was evaluated.

    “Multiple independent clones were isolated and Spring expression and function was evaluated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    For all experiments littermates were used as controls.

    “For all experiments littermates were used as controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    S1P cleaves and activates several transcription factors and other proteins, including ATF6, CREB3, CREB3L1, CREB4, and CREB3L3.

    “Accordingly, S1P cleaves and activates several transcription factors and other proteins.11,15 Other than SREBP1 and 2, 1,10 these include the ER-stress response-related transcription factor activating transcription factor 6 (ATF6), 16,17 cyclic AMP-responsive element binding proteins CREB3, 18 CREB3L1, 19 CREB4, 20 and CREB3L3.21”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [18]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [19]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Global ablation of SPRING in mice results in embryonic lethality, mirroring S1P and SCAP knockout models.

    “Global ablation of SPRING in mice results in embryonic lethality, 27 mirroring S1P and SCAP knockout models.41,42”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [41]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [42]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    S1P cleaves several proproteins at the C-terminus of the consensus motif RX(L,V,I)Z#.

    “Active S1P cleaves several proproteins at the C-terminus of the consensus motif RX(L,V,I)Z#”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    SPRING is required for adequate proteolytic processing of SREBPs and SREBP-dependent signaling.

    “We reported that SPRING is required for adequate proteolytic processing of SREBPs and SREBP-dependent signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Pharmacological or genetic inhibition of SREBP-cleavage by S1P prevents retrograde transport of SCAP and promotes SCAP degradation.

    “as pharmacological or genetic inhibition of SREBP-cleavage by S1P prevents retrograde transport of SCAP and promotes SCAP degradation.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Equal transfection efficiency was monitored by cotransfection with an expression plasmid for GFP or mCherry and was consistently comparable.

    “Equal transfection efficiency was monitored by cotransfection with an expression plasmid for GFP or mCherry and was consistently comparable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Impaired retrograde trafficking of SCAP from the Golgi to the ER results in functional SCAP deficiency and attenuated SREBP signaling.

    “We posited that this is caused, at least in part, due to impaired retrograde trafficking of SCAP from the Golgi to the ER, which results in functional SCAP deficiency and attenuated SREBP signaling.27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

31 of 31

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Citation 33 does not identify the named Hendrix study

    Minor

    The text attributes the liver-specific Spring knockout mice to Hendrix et al. at reference 33, but entry 33 in the provided References is a paper by Pernemalm et al. The Hendrix liver study appears instead as entry 26.

  • SPRING-S1P ectodomain experiment is assigned to two different figure panels

    Minor

    The results direct readers to Figure 1G, lane 8 for the ectodomain co-immunoprecipitation, but the Figure 1 caption assigns that experiment to panel H. Panel G is described as an experiment on FURIN and PCSK9 processing.

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Metadata

Authors
Hendrix, S., Tan, J. M. E., Ndoj, K., Kingma, J., Valiloo, M., Zijlstra, L. F., Ottenhoff, R., Seidah, N. G., Loregger, A., Kober, D. L., & Zelcer, N.
Affiliations
  • Amsterdam University Medical Centers (NL)
  • Montreal Clinical Research Institute (CA)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Zelcer, Noam
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2024-04-02
Volume
44
Issue
4
Pages
123-137
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1080/10985549.2024.2348711
PMC
PMC11110692
OpenAlex
W4396928541
Cited by
9
References
47
Citations by year
2026: 4 · 2025: 3 · 2024: 2
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular and Cellular Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
Funders
  • Netherlands Organization for Scientific Research (40-45200-98-21118)
  • CIHR foundation (#148363)
  • Canada Research Chair in Precursor Proteolysis (#950-231335, 4R00GM141261)
  • National Institutes of Health (MSCA-ITN-2020)
  • European Union (953489; EndoConnect)
  • ERC Consolidator (617376, Netherlands Organization for Scientific Research, NWO; 016.176.643, GENESIS, M.22.034)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
springs, SREBP, site-1 protease, sphingosine-1-phosphate, proteolytic maturation, Golgi trafficking, ATF6, lipid metabolism, transcriptional regulation, liver-specific knockout mice
MeSH terms
Animals, Endoplasmic Reticulum, Golgi Apparatus, Humans, Liver, Serine Endopeptidases, Signal Transduction, Mice, Knockout, Proprotein Convertases, Mice, Sterol Regulatory Element Binding Proteins, HEK293 Cells, Proteolysis

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