Stefins

Stefins are a subgroup of the cystatin superfamily, comprising intracellular cysteine protease inhibitors primarily of the cysteine cathepsin type. The two most studied members, stefin A (cystatin A) and stefin B (cystatin B), are encoded by the CST3‑related genes CST6 and CST7, respectively, and are expressed in a wide range of tissues, most notably in epithelial cells, leukocytes, and the central nervous system. Unlike the secreted type 2 cystatins, stefin molecules lack a signal peptide and function within the cytosol, where they regulate proteolysis by competitively binding the active sites of cathepsins B, H, and L, thereby modulating protein turnover, antigen processing, and apoptosis.

Structurally, stefins are small proteins of approximately 11 kDa, adopting a highly conserved α‑β fold consisting of a five‑strand β‑sheet wrapped around a central α‑helix. Three conserved motifs—Gly‑Gly‑Leu‐Val at the N‑terminus, a QXVXG loop, and a PW motif—form the protease‑binding interface. Their intracellular localization is regulated by post‑translational modifications such as phosphorylation, which can affect stability and subcellular distribution.

Clinically, alterations in stefin expression have been linked to several disorders. Deficiency of stefin B causes Unverricht‑Lundborg disease, a form of progressive myoclonus epilepsy, while overexpression of stefin A has been observed in certain cancers and may influence tumor invasiveness through modulation of cathepsin activity. In neurodegenerative research, stefin B is investigated for its role in neuroinflammation and neuronal survival. Ongoing studies aim to exploit stefin‑cathepsin interactions for therapeutic development in inflammatory, oncologic, and neurodegenerative diseases.