PACE4: a subtilisin-like endoprotease with unique properties

Mains, Richard E.; Berard, Carla A.; Denault, Jean‐Bernard; Zhou, An; Johnson, R. C.; Leduc, Richard

doi:10.1042/bj3210587

Cited by 58 publications

(47 citation statements)

References 85 publications

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“…Others investigating the biochemical properties of PACE4 have reported conflicting results on the Ca# + requirements of PACE4. Decroly et al [41] report that PACE4 activity towards a fluorogenic substrate was inhibited by 2 mM EDTA ; others, however, claim that PACE4 is relatively independent of Ca# + [42]. We cannot resolve this discrepancy at present.…”

Section: Discussioncontrasting

confidence: 41%

Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain

Sucic

Moehring

Inocencio

et al. 1999

Biochemical Journal

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PACE4 is a member of the eukaryotic subtilisin-like endoprotease family. The expression of human PACE4 in RPE.40 cells (furin-null mutants derived from Chinese hamster ovary K1 cells) resulted in the rescue of a number of wild-type characteristics, including sensitivity to Sindbis virus and the ability to process the low-density-lipoprotein receptor-related protein. Expression of PACE4 in these cells failed to restore wild-type sensitivity to Pseudomonas exotoxin A. Co-expression of human PACE4 in these cells with either a secreted form of the human insulin pro-receptor or the precursor form of von Willebrand factor resulted in both proproteins being processed; RPE.40 cells were unable to process either precursor protein in the absence of co-expressed PACE4. Northern analysis demonstrated that untransfected RPE.40 cells express mRNA species for four PACE4 isoforms, suggesting that any endogenous PACE4 proteins produced by these cells are either non-functional or sequestered in a compartment outside of the secretory pathway. In experiments in vitro, PACE4 processed diphtheria toxin and anthrax toxin protective antigen, but not Pseudomonas exotoxin A. The activity of PACE4 in vitro was Ca2+-dependent and, unlike furin, was sensitive to temperature changes between 22 and 37 °C. RPE.40 cells stably expressing human PACE4 secreted an endoprotease with the same Ca2+ dependence and temperature sensitivity as that observed in membrane fractions of these cells assayed in vitro. These results, in conjunction with other published work, demonstrate that PACE4 is an endoprotease with more stringent substrate specificity and more limited operating parameters than furin.

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Section: Discussioncontrasting

confidence: 41%

Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain

Sucic

Moehring

Inocencio

et al. 1999

Biochemical Journal

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“…In contrast, ␣ 1 PI, an inhibitor that does not block furin (data not shown) (51), blocks an enzyme that is up-regulated after day 7 of culture. This may well be a component of the plasminogen activator (PA)/plasmin cascade, since plasmin is inhibited by ␣ 1 PI and is a known activator of procollagenases (18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 83%

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

Milner¹,

Rowan²,

Sf³

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the role of furin-like enzymes in the proteolytic cascades leading to cartilage breakdown and to examine which collagenase(s) contribute to collagen degradation.Methods. Bovine nasal cartilage was stimulated to resorb with the addition of interleukin-1␣ (IL-1␣)/ oncostatin M (OSM) in the presence or absence of a furin inhibitor, Dec-RVKR-CH 2 Cl, or selective matrix metalloproteinase 1 (MMP-1) inhibitors. Collagen and proteoglycan levels were determined by assay of hydroxyproline and sulfated glycosaminoglycan, respectively. Collagenase and gelatinase activity were measured using 3 H-acetylated collagen and gelatin zymography, respectively.Results. The addition of Dec-RVKR-CH 2 Cl to stimulated cartilage reduced the release of collagen fragments and the levels of active collagenase and MMP-2, suggesting that furin-like enzymes are involved in the cascades leading to activation of procollagenases. At MMP inhibitor concentrations that selectively inhibit MMP-1, no inhibition of collagen release was observed, but increasing the concentration to the 50% inhibition concentration for MMP-13 resulted in a 50% blockage of collagen release. The addition of Dec-RVKR-CH 2 Cl to resorbing cartilage also partially blocked proteoglycan release, thus demonstrating a role for furin-activated enzymes in the pathways leading to proteoglycan degradation. Conclusion.Furin-like enzymes are involved in cascades leading to activation of procollagenases and degradation of collagen. MMP-13, which can be activated by furin-processed membrane-type 1 MMP-1, appears to be a major collagenase involved in collagen degradation induced by IL-1␣/OSM. Furin-like enzymes also appear to play a role in the pathways leading to proteoglycan degradation. These findings are of importance when considering proteinase inhibition as a target for therapeutic intervention in arthritic diseases.

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“…Furthermore, the overexpression of PC1 in cell lines that do not express endogenous PC1 does not seem to affect its fast propeptide cleavage (17). Finally, the slow maturation of recombinant PACE4 was similar to its endogenous counterpart (32). It therefore seems that overexpression of proprotein convertases does not have a pronounced effect on their maturation kinetics.…”

Section: Discussionmentioning

confidence: 64%

“…The conversion of pro-PACE4 (20,32) and pro-LPC (10), on the other hand, takes hours rather than minutes. The prosegments of both furin and LPC can act in trans as potent inhibitors of the enzymes themselves (33).…”

mentioning

confidence: 99%

Binding of BiP to the Processing Enzyme Lymphoma Proprotein Convertase Prevents Aggregation, but Slows Down Maturation

Creemers¹,

Loo²,

Plets³

et al. 2000

Journal of Biological Chemistry

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Lymphoma proprotein convertase (LPC) is a subtilisin-like serine protease of the mammalian proprotein convertase family. It is synthesized as an inactive precursor protein, and propeptide cleavage occurs via intramolecular cleavage in the endoplasmic reticulum. In contrast to other convertases like furin and proprotein convertase-1, propeptide cleavage occurs slowly. Also, both a glycosylated and an unglycosylated precursor are detected. Here we demonstrate that the unglycosylated precursor form of LPC is localized in the cytosol due to the absence of a signal peptide. Using a reducible cross-linker, we found that glycosylated pro-LPC is associated with the molecular chaperone BiP. In addition, we show that pro-LPC is prone to aggregation and forms large complexes linked via interchain disulfide bonds. BiP is associated mainly with non-aggregated pro-LPC and pro-LPC dimers and trimers, suggesting that BiP prevents aggregation. Overexpression of wild-type BiP or a dominant-negative BiP ATPase mutant resulted in reduced processing of pro-LPC. Taken together, these results suggest that binding of BiP to pro-LPC prevents aggregation, but results in slower maturation.

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PACE4: a subtilisin-like endoprotease with unique properties

Cited by 58 publications

References 85 publications

Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain

Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

Binding of BiP to the Processing Enzyme Lymphoma Proprotein Convertase Prevents Aggregation, but Slows Down Maturation

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