Deficiency inLystfunction leads to accumulation of secreted proteases and predisposition to mechanic stress-induced retinal detachment

Abstract

Chediak–Higashi syndrome , caused by mutations in the Lys osome T rafficking Regulator ( Lyst ) gene, is a recessive hypopigmentation disorder characterized by albinism, neuropathies, neurodegeneration , and defective immune response s , with e nlargement of lysosomes and lysosome-related organelles. Although recent studies have suggested that Lyst mutations impair the regulation of sizes of lysosome and lysosome-related organelle , the underlying pathogenic mechanism of Chediak–Higashi syndrome is still unclear. Here we show striking evidence that deficiency in LYST protein function leads to accumulation of photoreceptor outer segment phagosomes in retinal pigment epitheli al cells , and reduce s adhesion between photoreceptor outer segment and retinal pigment epithelial cells in a mouse model of Chediak–Higashi syndrome . In addition, we observe elevated levels of cathepsin s , matrix metallopeptidase ( MMP ) 3 and oxidative stress markers in the retinal pigment epitheli um of Lyst mutant s . Previous reports showed that impaired degradation of photoreceptor outer segment phagosomes causes elevated oxidative stress , which could consequently lead to increase s of cysteine cathepsins and MMPs in the extracellular matrix. T aken together , we conclude that the loss of LYST function causes accumulation of phagosomes in the retinal pigment epitheli um and elevation of several extracellular matrix -remodeling proteases through oxidative stress , which may, in turn, reduce retina l adhesion. Our work reveals previously unreported pathogenic events in the retinal pigment epitheli um caused by Lyst deficiency , which may place Chediak–Higashi syndrome patients at increased risk for retinal detachment . The same pathogenic events may be conserved in other professional phagocytic cells, such as macrophages in the immune system, contributing to overall Chediak–Higashi syndrome pathology.