cystatins

Cystatins are a superfamily of cysteine protease inhibitors that regulate the activity of cysteine proteases such as cathepsins within cells and in the extracellular milieu. By binding reversibly to target proteases, they limit proteolysis and help maintain tissue homeostasis. The cystatin superfamily is conventionally divided into three groups: type 1 stefins, type 2 cystatins, and type 3 kininogens, reflecting differences in localization and structure.

Type 1 stefins are intracellular, lack signal peptides and disulfide bonds, and are typically small proteins of about 11–14 kDa. Type 2 cystatins are secreted or bound to extracellular fluids; they usually contain signal peptides and disulfide bonds, and weigh around 13–15 kDa. Type 3 cystatins, also called kininogens, are high-molecular-weight plasma proteins that can function as protease inhibitors and also serve as precursors for kinins.

Within their inhibitory action, cystatins target a range of cathepsins (B, L, S, H) and related enzymes, thereby influencing processes such as antigen processing, immune responses, extracellular matrix turnover, and bone remodeling. They also participate in regulation of inflammation and may affect signaling pathways in neural tissue.

Clinical relevance: Cystatin C, a type 2 cystatin, is a widely used biomarker for estimating glomerular filtration rate and kidney function. Altered cystatin levels have been reported in cancer, neurodegenerative diseases, and inflammatory disorders, making cystatins a focus of diagnostic and translational research.

Notable members include cystatin C (CST3), cystatin B, and cystatin S, among others. The cystatin family shows broad evolutionary conservation and tissue-specific expression patterns that reflect its roles in protease regulation and tissue homeostasis.