βA3/A1-crystallin: More than a lens protein

Abstract

Crystallins, the highly abundant proteins of the ocular lens, are essential determinants of the transparency and refractivity required for lens function. Initially thought to be lens-specific and to have evolved as lens proteins, it is now clear that crystallins were recruited to the lens from proteins that existed before lenses evolved. Crystallins are expressed outside of the lens and most have been shown to have cellular functions distinct from their roles as structural elements in the lens. For one major crystallin group, the β/γ-crystallin superfamily, no such functions have yet been established. We have explored possible functions for the polypeptides (βA3- and βA1-crystallins) encoded by Cryba1, one of the 6 β-crystallin genes, using a spontaneous rat mutant and genetically engineered mouse models. βA3- and βA1-crystallins are expressed in astrocytes and retinal pigment epithelial (RPE) cells. In both cell types, these proteins appear to be required for the proper acidification of the lysosomes. In RPE cells, elevated pH in the lysosomes is shown to impair the critical processes of phagocytosis and autophagy, leading to accumulation of undigested cargo in (auto) phagolysosomes. We postulate that this accumulation may cause pathological changes in the cells resembling some of those characteristic of age-related macular degeneration (AMD). Our studies also suggest an important regulatory function of βA3/A1-crystallin in astrocytes. We provide evidence that the cellular function of βA3/A1-crystallin involves its interaction with V-ATPase, the proton pump responsible for acidification of the endolysosomal system.

βA3/A1-crystallin and persistent fetal vasculature (PFV) disease of the eye

“…Long thought to be proteins expressed only in the lens, α-crystallins and the β/γ-crystallin superfamily are now known to pre-date the evolution of the lens [26]. Further, these proteins are not lens-specific and have cellular functions in addition to their structural roles in the lens.…”

The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling

“…Crystallins are highly abundant proteins of the lens, essential for maintaining its transparency and refractivity. In addition to their roles as structural elements in the lens, crystallins may also have diverse functions in other parts of the eye (Horwitz, ; Piatigorsky, ; Zigler & Sinha, ). βA3/A1‐crystallin, a member of the β‐crystallin subfamily encoded by the Cryba1 gene, is also expressed in retinal pigmented epithelial (RPE) cells and astrocytes (Parthasarathy et al ., ).…”

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

“…More importantly, alpha-crystallins show RGC protective effects after ONC 80 and neuroprotective effects of beta-crystallin B2 have been extensively studied in the context of RGC damage and survival models, as well as RGC axonal outgrowth 45,81 . Additionally, crystallins can also be linked to age related macular degeneration, and altered crystallins lead to impaired lysosomal clearance in the retinal pigment epithelium 82,83 , however they have not been linked to AMBRA1 so far. Studies have been able to link crystallins (CRYBA1 and CRAYAB) to ATP6V1A expression.…”