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Title: Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

Author
item LEI, LYU - Sichuan University
item WHITCOMB, ELIZABETH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JIANG, SHUHONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CHANG, MIN-LEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GU, YUMEI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item DUNCAN, MELINDA - University Of Delaware
item CVEKL, ALES - Albert Einstein College Of Medicine
item WANT, WEI-LIN - Albert Einstein College Of Medicine
item LIMI, SAIMA - Albert Einstein College Of Medicine
item RENEKER, LIXING - University Of Missouri
item SHANG, FU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item DU, LINFANG - Sichuan University
item TAYLOR, ALLEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/2/2015
Publication Date: 3/1/2016
Citation: Lei, L., Whitcomb, E., Jiang, S., Chang, M., Gu, Y., Duncan, M.K., Cvekl, A., Want, W., Limi, S., Reneker, L.W., Shang, F., Du, L., Taylor, A. 2016. Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. Journal of Federation of American Societies for Experimental Biology. 30(3):1087-1095. doi: 10.1096/fj.15-278036.

Interpretive Summary: Cataract is the leading cause of blindness worldwide. In order to create a clear lens, the internal cells of the eye lens, called lens fiber cells, must remove their nuclei. How this denucleation process happens has been a mystery for over 100 years, and failure of lens fiber cell denucleation is associated with congenital cataracts. We found that mechanisms that direct the unidirectional process of lens fiber cell denucleation are analogous to the cyclic processes associated with cell division. Specifically, we found that lens-specific mutations elicit an unfolded-protein response in vivo accumulate p27, a major controller of cell division. Since p27 also inhibits another major controlling enzyme called cyclin-dependent kinase 1 (Cdk1,) it is not surprising that it is inhibited in the cataractous lenses. In lenses that express mutant ubiquitin, K6W-Ub, we also observed accumulated p27 and failed lens fiber cell denucleation. Associated with the delayed lens fiber cell denucleation is decreased laminA/C phosphorylation and metaphase arrest. Taken together, these data indicate that accumulation of p27, whether related to the unfolded-protein response or not, prevents the phosphorylation of lamin A/C and lens fiber cell denucleation in maturing lens fiber cells in vivo, as well as in dividing human lens epithelial cells. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of lens fiber cell nuclei.

Technical Abstract: Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous. Although a UPR was not detected in lenses expressing K6W-Ub, they also accumulated p27 and showed failed LFCD. Induction of a UPR in human lens epithelial cells (HLECs) also induced accumulation of p27 associated with decreased levels of S-phase kinase-associated protein (Skp)-2, a ubiquitin ligase that regulates mitosis. These cells also showed decreased lamin A/C phosphorylation and metaphase arrest. The suppression of lamin A/C phosphorylation and metaphase transition induced by the UPR was rescued by knockdown of p27. Taken together, these data indicate that accumulation of p27, whether related to the UPR or not, prevents the phosphorylation of lamin A/C and LFCD in maturing LFCs in vivo, as well as in dividing HLECs. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of LFC nuclei.