Dataset Information

Age-related cleavages of crystallins in human lens cortical fibre cells generate a plethora of endogenous peptides and high molecular weight complexes

ABSTRACT: Age-related breakdown of lenticular crystallins is associated with lenticular disorders such as cataract. Despite playing a critical role in maintaining lens homeostasis, the mechanism(s) and consequences of this phenomenon are not well understood. Utilising a proteomic-based approach, this study characterised 238 endogenous peptides derived from age-related crystallin breakdowns present in the cortical tissues of young, middle-age and old human lenses. Quantitative mass spectrometry analysis showed that the concentration of a prominent crystallin breakdown product in the lens increased significantly with age, which, coupled with the age-related increase in variety of the LMW crystallin peptide in the lens cortex, suggests that a major crystallin breakdown event taking place in the human lens cortex shortly after middle-age. In-depth analysis on the crystallin peptide terminal amino acids indicate the presence of trypsin-like proteolysis in the lens cortical cells, providing useful information on the mechanism(s) that contribute to crystallin breakdown in the aging human lens. Taken together, this work enhances our understanding on the age-related crystallin breakdown process in the cortical tissues of the human lens.

INSTRUMENT(S): QSTAR

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lens Cortex

SUBMITTER: Xiaomin Song

LAB HEAD: Xiaomin Song

PROVIDER: PXD001630 | Pride | 2016-09-29

REPOSITORIES: Pride

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Age-related cleavages of crystallins in human lens cortical fiber cells generate a plethora of endogenous peptides and high molecular weight complexes.

Su Shih-Ping SP Song Xiaomin X Xavier Dylan D Aquilina J Andrew JA

Proteins 20150819 10

Low molecular weight peptides derived from the breakdown of crystallins have been reported in adult human lenses. The proliferation of these LMW peptides coincides with the earliest stages of cataract formation, suggesting that the protein cleavages involved may contribute to the aggregation and insolubilization of crystallins. This study reports the identification of 238 endogenous LMW crystallin peptides from the cortical extracts of four human lenses representing young, middle and old-age hum ...[more]

PMID: 26238763

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Project description:Although majority of the genes linked to pediatric cataract exhibit lens fiber cell-enriched expression, our understanding of gene regulation in these cells is limited to function of just eight transcription factors and largely in the context of crystallins. Here, we identify small Maf transcription factors MafG and MafK as regulators of several non-crystallin human cataract genes in fiber cells and establish their significance to cataract. We applied a bioinformatics tool for cataract gene discovery iSyTE to identify MafG and its co-regulators in the lens, and generated various null-allelic combinations of MafG:MafK mouse mutants for phenotypic and molecular analysis. By age 4-months, MafG-/-:MafK+/- mutants exhibit lens defects that progressively develop into cataract. High-resolution phenotypic characterization of MafG-/-:MafK+/- lens reveals severe defects in fiber cells, while microarrays-based expression profiling identifies 97 differentially regulated genes (DRGs). Integrative analysis of MafG-/-:MafK+/- lens-DRGs with 1) binding-motifs and genomic targets of small Mafs and their regulatory partners, 2) iSyTE lens-expression data, and 3) interactions between DRGs in the String database, unravels a detailed small Maf regulatory network in the lens, several nodes of which are linked to human cataract. This analysis prioritizes 36 highly promising candidates from the original 97 DRGs. Significantly, 8/36 (22%) DRGs are associated with cataracts in human (GSTO1, MGST1, SC4MOL, UCHL1) or mouse (Aldh3a1, Crygf, Hspb1, Pcbd1), suggesting a multifactorial etiology that includes elevation of oxidative stress. These data identify MafG and MafK as new cataract-associated candidates and define their function in regulating largely non-crystallin genes linked to mouse and human cataract. Microarray comparision of lenses from mixed background (129Sv/J, C57BL/6J, and ICR) control (MafG+/-:MafK+/-; no-cataract) and compound (MafG-/-:MafK+/-; cataract) mouse mutants

			Action	DRS
	FIG5.pdf	Pdf
	UOW_1 (F089248).mzid_UOW_1_(F089248).pride.mgf.gz	Mzid
	UOW_1 (F089248).pride.mztab.gz	Mztab
	UOW_1.mgf	Mgf
	UOW_1.pride.mgf.gz	Mgf