title: Regulation of the membrane mucin Muc4 in corneal epithelial cells by proteosomal degradation and TGF-beta.
abstract: MUC4 is a heterodimeric membrane mucin, composed of a mucin subunit ASGP-1 (MUC4alpha) and a transmembrane subunit ASGP-2 (MUC4beta), which has been implicated in the protection of epithelial cell surfaces. In the rat stratified corneal epithelium Muc4 is found predominantly in the most superficial cell layers. Since previous studies in other tissues have shown that Muc4 is regulated by TGF-beta via a proteosomal degradation mechanism, we investigated the regulation of corneal Muc4 in stratified cultures of corneal epithelial cells. Application of proteosome or processing inhibitors led to increases in levels of Muc4, particularly in the basal and intermediate levels of the stratified cultures. These changes were accompanied by increases in Muc4 ubiquitination, chaperone association and incorporation into intracellular aggresomes. In contrast, treatment with TGF-beta resulted in reduced levels of Muc4, which were reversed by proteosome inhibition. The results support a model in which Muc4 precursor is synthesized in all layers of the corneal epithelium, but Muc4 is degraded in basal and intermediate layers by a proteosomal mechanism at least partly dependent on TGF-beta inhibition of Muc4 processing.
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lomako
authors.forename: Wieslawa M
authors.initials: WM
authors.lastname: Lomako
authors.forename: Coralie A
authors.initials: CA
authors.lastname: Carothers Carraway
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000187:drug effects / Q000378:metabolism*; D008361:Mannosidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055264:Mucin-4 / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000470:Alkaloids; D037282:Calreticulin; D015853:Cysteine Proteinase Inhibitors; C524660:Muc4 protein, rat; D055264:Mucin-4; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D016212:Transforming Growth Factor beta; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C065629:kifunensine; D037281:Calnexin; D008361:Mannosidases; D046988:Proteasome Endopeptidase Complex