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PMID:22864553

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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


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CATS

involved_in

GO:0016485: protein processing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CATS

involved_in

GO:0010447: response to acidic pH

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CATS

GO:0006508: proteolysis

ECO:0000314:

P

Figure 7

complete
CACAO 5504

HUMAN:CATS

GO:2001259: positive regulation of cation channel activity

ECO:0000314:

P

Figure 2: ENaC (cation channel) activation by Cathepsin S

complete
CACAO 5172

HUMAN:CATS

GO:2001258: negative regulation of cation channel activity

ECO:0000314:

P

Figure 3: ENaC (cation channel) inhibition by cathepsin-S inhibitor LHVS

complete
CACAO 5178

HUMAN:CATS

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
CACAO 5191

HUMAN:CATS

GO:0008234: cysteine-type peptidase activity

ECO:0000314:

F

Figure 2: Cysteine protease cathepsin-S activates ENaC (cation channel).

complete
CACAO 5196

HUMAN:CATS

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
CACAO 5204

HUMAN:CATS

GO:0010447: response to acidity

ECO:0000314:

P

Figure 5: Cathepsin-S can activate ENaC in an acidic environment.

complete
CACAO 5210

HUMAN:CATS

GO:0030162: regulation of proteolysis

ECO:0000314:

P

Figure 6.

complete
CACAO 5723

HUMAN:CATS

GO:0016485: protein processing

ECO:0000314:

P

Figure 6

complete
CACAO 5777

HUMAN:CATS

involved_in

GO:2001259: positive regulation of cation channel activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CATS

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CATS

GO:2001259: positive regulation of cation channel activity

ECO:0000314:

P

Figure 9: Activation of ENaC (cation channel) by cathepsin-S.

complete
CACAO 5193

MOUSE:CATS

involved_in

GO:2001259: positive regulation of cation channel activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SCNNG

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
CACAO 5364

HUMAN:SCNNG

enables

GO:0005216: ion channel activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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