Abstract
Lysosomes are important for proper functioning of the retinal pigment epithelial (RPE) cells. RPE cells have a daily burden of phagocytosis of photoreceptor outer segments (POS) and also degrade cellular waste by autophagy. Here, we identified the role of Zinc-finger protein with KRAB and SCAN domains 3 (ZKSCAN3) in co-ordinate regulation of lysosomal function and autophagy in the RPE. Our studies show that in the RPE, ZKSCAN3 is predominantly nuclear in healthy cells and its nuclear expression is reduced upon nutrient deprivation. siRNA-mediated knockdown of ZKSCAN3 results in de-repression of some of the ZKSCAN3 target genes. Knockdown of ZKSCAN3 also resulted in an induction in autophagy flux, increase in the number of functional lysosomes and accompanied activation of lysosomal cathepsin B activity in ARPE-19 cells. We also demonstrated that inhibition of P38 mitogen-activated protein kinase (MAPK) retains ZKSCAN3 in the nucleus in nutrient-deprived cells. In summary, our studies elucidated the role of ZKSCAN3 as a transcriptional repressor of autophagy and lysosomal function in the RPE.
Highlights
The retinal pigment epithelium (RPE) is a monolayer of cells that performs several crucial functions vital for maintaining retinal homeostasis
We investigated the role of ZKSCAN3 in the RPE and the underlying regulatory mechanisms that contribute to the de-repression of ZKSCAN3 target genes in response to cellular stress
Remarkable progress has been made in our understanding of the molecular events that coordinately regulate the transcription of genes involved in the lysosomal and autophagy pathway
Summary
The retinal pigment epithelium (RPE) is a monolayer of cells that performs several crucial functions vital for maintaining retinal homeostasis. A cellular degradation pathway, is crucially important to remove damaged structures and metabolic byproducts and reduce cellular accumulation in the RPE [2]. Dysfunctional autophagy process is known to result in impairment of RPE homeostasis, leading to age-related macular degeneration (AMD) [2]. A crucially important stage in the autophagy process is the fusion of autophagosomes with lysosomes to form autophagolysosomes, where the autophagy substrates are degraded by the lysosomal hydrolases [4]. Since lysosomes are important in the terminal stages of the autophagy process, impaired lysosomal function can have significant implications on the autophagy pathway [3]. Age-related decline in lysosomal function is known to result in accumulation of phagocytosed outer segments and autophagic cellular substrates within the RPE, leading to impaired RPE function [6,7]. Oxidized lipoproteins contribute to a decline in lysosomal function by inhibiting the activity of lysosomal proteolytic enzymes [10]
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