Keratins modulate colonocyte electrolyte transport via protein mistargeting.
The function of intestinal keratins is unknown, although keratin 8 (K8)-null mice develop colitis, hyperplasia, diarrhea, and mistarget jejunal apical markers. We quantified the diarrhea in K8-null stool and examined its physiologic basis. Isolated crypt-units from K8-null and wild-type mice have similar viability. K8-null distal colon has normal tight junction permeability and paracellular transport but shows decreased short circuit current and net Na absorption associated with net Cl secretion, blunted intracellular Cl/HCO3-dependent pH regulation, hyperproliferation and enlarged goblet cells, partial loss of the membrane-proximal markers H,K-ATPase-beta and F-actin, increased and redistributed basolateral anion exchanger AE1/2 protein, and redistributed Na-transporter ENaC-gamma. Diarrhea and protein mistargeting are observed 1-2 d after birth while hyperproliferation/inflammation occurs later. The AE1/2 changes and altered intracellular pH regulation likely account, at least in part, for the ion transport defects and hyperproliferation. Therefore, colonic keratins have a novel function in regulating electrolyte transport, likely by targeting ion transporters to their cellular compartments.
Palo Alto VA Medical Center, 3801 Miranda Ave., Mail code 154J, Palo Alto, CA 94304, USA.
Diana M
DM
Toivola
Selvi
S
Krishnan
Henry J
HJ
Binder
Satish K
SK
Singh
M Bishr
MB
Omary
D000367:Age Factors; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D015415:Biomarkers; D002034:Bumetanide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000033:anatomy & histology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D004573:Electrolytes / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology; D053533:Keratin-8; D007633:Keratins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology; D010641:Phenotype; D012964:Sodium / Q000378:metabolism
D001639:Bicarbonates; D015415:Biomarkers; D002712:Chlorides; D004232:Diuretics; D004573:Electrolytes; D053533:Keratin-8; C486595:Krt8 protein, mouse; D009579:Nitrobenzoates; D002034:Bumetanide; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D007633:Keratins; D012964:Sodium; D000242:Cyclic AMP