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Published online 8 March 2004. doi:10.1083/jcb.200308103
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 6, 911-921
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Article

 Keratins modulate colonocyte electrolyte transport via protein mistargeting

Diana M. Toivola1,2, Selvi Krishnan4, Henry J. Binder3, Satish K. Singh4, and M. Bishr Omary1,2

1 Palo Alto VA Medical Center, Palo Alto, CA 94304
2 Stanford University School of Medicine Digestive Disease Center, Stanford, CA 94305
3 Yale University School of Medicine, New Haven, CT 06520
4 Boston Medical Center, Boston, MA 02118

Address correspondence to Bishr Omary, Palo Alto VA Medical Center, 3801 Miranda Ave., Mail code 154J, Palo Alto, CA 94304. Fax: (650) 852-3259

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-ß 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.

Key Words: ion transport; diarrhea; intestine; intermediate filaments; cytoskeleton

D.M. Toivola and S. Krishnan contributed equally to this work.

Abbreviations used in this paper: CFTR, cystic fibrosis transmembrane receptor; DRA, down-regulated in adenoma; IF, intermediate filament; K, keratin; NHE3, Na/H exchanger 3; pHi, intracellular pH.


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