Identification of Vimentin as a Novel Target of HSF4 in Lens Development and Cataract by Proteomic Analysis

Abstract

These findings indicate that HSF4 represses vimentin gene expression via the HSE-like element. The loss of HSF4 function results in an increase in vimentin expression in Hsf4(tm1Xyk)-knockout mice and affects lens differentiation, particularly impairing the denucleation of lens fiber cells. These events appear to implicate a molecular mechanism in abnormal lens development and cataract formation in Hsf4(tm1Xyk)-knockout mice. The HSF4-vimentin axis appears to be a new target for developing anti-cataract drugs, especially for those cataracts resulting from aberrations in HSF4 expression.

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

“… 52 Secondly, HSF4 relies on its target gene products α B-crystallin and vimentin to stabilize p53. 16 α B-crystallin can interact with p53 to stabilize the later. 58 The HSF4-regulated upregulation of p53 can initiate cell apoptosis signaling, leading to the apoptotic cleavage of vimentin.…”

“…These genes include the ones encoding heat shock proteins (Hsp70, Hsp60 and Hsp27), diverse types of γ -crystallins, various forms of fibroblast growth factors or the cognate receptor (FGF1, 2, 4, 7 and FGFR1), the beaded filament proteins (Bfsp1/2) 12 , 13 , 14 and several other target genes (SKAP2, Vimentin). 15 , 16 Besides the knockout models, the HSF4 p.Arg116His mutation and the Hsf4 (exon1)-DBD-EGFP hybrid gene transgenic mouse models have also been constructed. Both models developed postnatal lamellar cataract, which is similar to the phenotype caused by the mutations in the DBD of human HSF4 gene.…”

Lens Crystallin Modifications and Cataract in Transgenic Mice Overexpressing Acylpeptide Hydrolase

“…Further, there was suppression of the lens fiber cell elongation in vimentin-induced cataract model, whereas this was not obvious in APH model. Other studies have also suggested a role for vimentin in cataract development (61,62). Loss of HSF4 function has been shown to reduce crystallin levels, which activates vimentin expression (59).…”

Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin

“…Its expression is regulated by growth factors, and it belongs to the early-response-competence gene fam- ily (Rittling et al 1985;Ferrari et al 1986). Several investigations have suggested the involvement of vimentin in growth and differentiation of different systems, including muscle (Olson and Capetanaki 1989), lens Mou et al 2010), and osteoblasts (Lian et al 2009). In all these cases, overexpression of vimentin, ectopic or owing to the absence of its repressor HSF4 (Mou et al 2010), inhibits differentiation.…”

“…Several investigations have suggested the involvement of vimentin in growth and differentiation of different systems, including muscle (Olson and Capetanaki 1989), lens Mou et al 2010), and osteoblasts (Lian et al 2009). In all these cases, overexpression of vimentin, ectopic or owing to the absence of its repressor HSF4 (Mou et al 2010), inhibits differentiation. The mechanism of this inhibition has been further revealed in the case of osteoblasts in which differentiation is suppressed through direct binding of the vimentin first leucine zipper (LZ) domain to the osteoblast-specific LZ-containing transcription factor ATF-4 (Lian et al 2009).…”