Abnormal expression of collagen IV in lens activates unfolded protein response resulting in cataract.
Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1(+/Deltaex40) mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.
Firtina
Zeynep
Z
Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, USA.
Danysh
Brian P
BP
Bai
Xiaoyang
X
Gould
Douglas B
DB
Kobayashi
Takehiro
T
Duncan
Melinda K
MK
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics; D002386:Cataract / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D024141:Collagen Type IV / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes / Q000235:genetics; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D051702:Activating Transcription Factor 6; D001324:Autoantigens; D024141:Collagen Type IV; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C057112:type IV collagen alpha3 chain; C486556:Ern2 protein, mouse