GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.
PMID:22864553
Citation |
Haerteis, S, Krappitz, M, Bertog, M, Krappitz, A, Baraznenok, V, Henderson, I, Lindström, E, Murphy, JE, Bunnett, NW and Korbmacher, C (2012) Proteolytic activation of the epithelial sodium channel (ENaC) by the cysteine protease cathepsin-S. Pflugers Arch. 464:353-65 |
---|---|
Abstract |
Proteolytic processing of the amiloride-sensitive epithelial sodium channel (ENaC) by serine proteases is known to be important for channel activation. Inappropriate ENaC activation by proteases may contribute to the pathophysiology of cystic fibrosis and could be involved in sodium retention and the pathogenesis of arterial hypertension in the context of renal disease. We hypothesized that in addition to serine proteases, cathepsin proteases may activate ENaC. Cathepsin proteases belong to the group of cysteine proteases and play a pathophysiological role in inflammatory diseases. Under pathophysiological conditions, cathepsin-S (Cat-S) may reach ENaC in the apical membrane of epithelial cells. The aim of this study was to investigate the effect of purified Cat-S on human ENaC heterologously expressed in Xenopus laevis oocytes and on ENaC-mediated sodium transport in cultured M-1 mouse renal collecting duct cells. We demonstrated that Cat-S activates amiloride-sensitive whole-cell currents in ENaC-expressing oocytes. The stimulatory effect of Cat-S was preserved at pH 5. ENaC stimulation by Cat-S was associated with the appearance of a γENaC cleavage fragment at the plasma membrane indicating proteolytic channel activation. Mutating two valine residues (V182 and V193) in the critical region of γENaC prevented proteolytic activation of ENaC by Cat-S. Pre-incubation of the oocytes with the Cat-S inhibitor morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl (LHVS) prevented the stimulatory effect of Cat-S on ENaC. In contrast, LHVS had no effect on ENaC activation by the prototypical serine proteases trypsin and chymotrypsin. Cat-S also stimulated ENaC in differentiated renal epithelial cells. These findings demonstrate that the cysteine protease Cat-S can activate ENaC which may be relevant under pathophysiological conditions. |
Links |
PubMed PMC3448907 Online version:10.1007/s00424-012-1138-3 |
Keywords |
|
edit table |
Significance
Annotations
Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
---|---|---|---|---|---|---|---|---|
involved_in |
GO:0016485: protein processing |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
involved_in |
GO:0010447: response to acidic pH |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
GO:0006508: proteolysis |
ECO:0000314: |
P |
Figure 7 |
complete | ||||
GO:2001259: positive regulation of cation channel activity |
ECO:0000314: |
P |
Figure 2: ENaC (cation channel) activation by Cathepsin S |
complete | ||||
GO:2001258: negative regulation of cation channel activity |
ECO:0000314: |
P |
Figure 3: ENaC (cation channel) inhibition by cathepsin-S inhibitor LHVS |
complete | ||||
GO:2001258: negative regulation of cation channel activity |
ECO:0000315: |
P |
Figure 8: Mutating two putative neutrophil elastase cleavage sites prevents proteolytic activation of ENaC by cathepsin-S. |
complete | ||||
GO:0008234: cysteine-type peptidase activity |
ECO:0000314: |
F |
Figure 2: Cysteine protease cathepsin-S activates ENaC (cation channel). |
complete | ||||
GO:0097179: protease inhibitor complex |
ECO:0000314: |
C |
Figure 3: Cysteine protease Cathepsin-S covalently binds to the vinylsulfone residue and inhibits ENaC (cation channel) activation. |
complete | ||||
GO:0010447: response to acidity |
ECO:0000314: |
P |
Figure 5: Cathepsin-S can activate ENaC in an acidic environment. |
complete | ||||
GO:0030162: regulation of proteolysis |
ECO:0000314: |
P |
Figure 6. |
complete | ||||
GO:0016485: protein processing |
ECO:0000314: |
P |
Figure 6 |
complete | ||||
involved_in |
GO:2001259: positive regulation of cation channel activity |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
involved_in |
GO:0006508: proteolysis |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
GO:2001259: positive regulation of cation channel activity |
ECO:0000314: |
P |
Figure 9: Activation of ENaC (cation channel) by cathepsin-S. |
complete | ||||
involved_in |
GO:2001259: positive regulation of cation channel activity |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
GO:0005216: ion channel activity |
ECO:0000315: |
F |
"ENaC stimulation by Cat-S was associated with the appearance of a γENaC cleavage fragment at the plasma membrane indicating proteolytic channel activation." Figures 7 and 8 demonstrate this association. |
complete | ||||
enables |
GO:0005216: ion channel activity |
ECO:0000315: mutant phenotype evidence used in manual assertion |
F |
Seeded From UniProt |
complete | |||
See also
References
See Help:References for how to manage references in GONUTS.