Small Leucine-Rich Proteoglycans (SLRPs) in the Retina

Abstract

Retinal diseases such as age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and diabetic retinopathy (DR) are the leading causes of visual impairment worldwide. There is a critical need to understand the structural and cellular components that play a vital role in the pathophysiology of retinal diseases. One potential component is the family of structural proteins called small leucine-rich proteoglycans (SLRPs). SLRPs are crucial in many fundamental biological processes involved in the maintenance of retinal homeostasis. They are present within the extracellular matrix (ECM) of connective and vascular tissues and contribute to tissue organization and modulation of cell growth. They play a vital role in cell-matrix interactions in many upstream signaling pathways involved in fibrillogenesis and angiogenesis. In this comprehensive review, we describe the expression patterns and function of SLRPs in the retina, including Biglycan and Decorin from class I; Fibromodulin, Lumican, and a Proline/arginine-rich end leucine-rich repeat protein (PRELP) from class II; Opticin and Osteoglycin/Mimecan from class III; and Chondroadherin (CHAD), Tsukushi and Nyctalopin from class IV.

Keywords: PRELP; biglycan; chondroadherin; decorin; fibromodulin; lumican; nyctalopin; opticin; osteoglycin/mimecan; retina; small leucine rich proteoglycans (SLRP); tsukushi.

Figure 1

Classification and gene–protein information of known retinal SLRPs. Biglycan and decorin belong to class I SLRPs. They harbor chondroitin or dermatan sulfate side chains and have a protein core made of 12 LRRs. Their N-terminal cysteine clusters follow the sequence C_x3C_xC_x6C. Fibromodulin, lumican, and PRELP/Prolargin belong to class II SLRPs. Class II SLRPs contain N-linked keratan sulfate and also have a protein core made of 12 LRRs. Their N-terminal cysteine cluster has the sequence C_X3C_XC_X9C. Opticin and osteoglycin/mimecan are class III SLRPs. They both have a protein core made of 7 LRRs and a N-terminal cysteine cluster sequence of C_X2C_XC_X6C. Osteoglycin/mimecan has a N-linked keratan sulfate side chain. Fibromodulin and lumican from class II and opticin and osteoglycin/mimecan from class III have clusters of tyrosine sulfate residues near their N-terminus. Chondroadherin (CHAD), tsukushi, and nyctalopin are class IV SLRPs. They have a protein core made of 11–13 LRRs and a N-terminal cysteine cluster sequence of C_X3C_XC_X6-17C. Class IV SLRPs do not have ear repeats. CHAD harbors a N-linked keratan sulfate side chain, and clusters of lysine and arginine at its C-terminus. Molecular weight represents SLRP core proteins without glycosylation.

Figure 2

Decorin’s versatility in the retina. The class I horseshoe-shaped SLRP, decorin has a protein core made of 12 leucine rich repeats (LRRs) which are flanked by cysteine rich residues. Their GAG side chains are typically chondroitin/dermatan sulfate. Under hypoxic conditions, decorin levels decreased, which can be rescued with triamcinolone acetonide. Barrier permeability can be compromised during high glucose conditions. Decorin has been reported to increase transepithelial resistance, and increase tight junction proteins such as occludin and Zonula Occludens-1 (ZO-1). Decorin can also regulate angiogenesis by exhibiting both pro- and anti-angiogenic capabilities. Decorin is a pan-receptor tyrosine kinase (RTK) inhibitor and has been shown to bind and inhibit Rac1, HIFα, VEGF, TGFβ, and TNFα. Decorin can also reduce proteins involved in fibrillogenesis such as collagen, αSMA, laminin, vimentin and fibronectin. Furthermore, decorin activate matrix metalloproteinases (MMPs) and reduce tissue inhibitors of metalloproteinases (TIMPs) to help prevent epithelial mesenchymal transitioning (EMT).