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Ke Liu, David Chin, Junmin Peng, Andrea Caceres, Fu Shang, Allen Taylor; Proteomic Support For Essential Roles For The Ubiquitin Proteasome System In Directing Lens Differentiation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2784.
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© ARVO (1962-2015); The Authors (2016-present)
Recent data indicate that the Ubiquitin Proteasome System (UPS) regulates a broad range of cellular behavior including differentiation in the vertebrate lens (Caceres PLoS One. 2010 5(10):e13331). The mechanisms by which the UPS mediates these activities remain to be elucidated. To determine molecular mechanisms by which the UPS regulates lens differentiation, we compared the protein profiles of lenses from wild type and transgenic mouse that expresses an ubiquitin mutant, K6W-Ubiquitin, against a wt background.
A UPS deficient lens model was built by specifically expressing a K6W-ubiquitin mutant of ubiquitin in the lens of mice (Caceres PLoS One. 2010 5(10):e13331). K6W-ubiquitin is conjugation competent but fails to support degradation via the UPS. Proteins in lysates of mutant and wild type lenses were analyzed by LC-MS/MS.
Using spectral counts as a metric, only ~2% of the proteome was different between lenses in which K6W-Ubiquitin was expressed against a wild type background vs. lenses in which only wild type ubiquitin was expressed. The proteins with greatest expression differences were filensin, vimentin, fodrin (spectrin alpha 2) and Tdrd7. Western blotting verified the MS data, confirming that levels of filensin, vimentin, fodrin and Tdrd7 were regulated by UPS and that differentiation is delayed in lenses in which the transgene is expressed.
Our results identified for the first time substrates of UPS which participate the regulation of lens differentiation and provide valuable data for future research of lens diseases. Interestingly, filensin is found in unique cytoskeletal elements, beaded filaments, and mutations in this gene have been associated with juvenile-onset, progressive cataracts and Dowling-Meara epidermolysis bullosa simplex. Vimentin is another component of the cytoskeletin. Antifodrin antibodies are an indicator of Sjogren’s syndrome, the 2nd commonest autoimmune disease and one that is associated with dry eye.
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