Abstract
Regulation of the equilibrium between proteases and their inhibitors is fundamental to health maintenance. Consequently, developing a means of targeting protease activity to promote tissue regeneration and inhibit inflammation may offer a new strategy in therapy development for diabetes and other diseases. Specifically, recent efforts have focused on serine protease inhibitors, known as serpins, as potential therapeutic targets. The serpin protein family comprises a broad range of protease inhibitors, which are categorized into 16 clades that are all extracellular, with the exception of Clade B, which controls mostly intracellular proteases, including both serine- and papain-like cysteine proteases. This review discusses the most salient, and sometimes opposing, views that either inhibition or augmentation of protease activity can bring about positive outcomes in pancreatic islet biology and inflammation. These potential discrepancies can be reconciled at the molecular level as specific proteases and serpins regulate distinct signaling pathways, thereby playing equally distinct roles in health and disease development.
Highlights
Protease activity is critical for the survival of multicellular organisms
When a serpin molecule binds to its target protease, the reactive center loop (RCL) is cleaved by the active site of the protease, which results in a conformational shift of the serpin from the ‘stressed’ to the
Cathepsin L is a major lysosomal cysteine protease that is important for antigen presentation in macrophages and cortical epithelia cells, where it is responsible for degradation of the invariant chain [47]
Summary
Protease activity is critical for the survival of multicellular organisms. Proteases break down peptide bonds, resulting in irreversible posttranslational protein modifications. After the RCL is cut, the serpin undergoes a transitionserpin–enz complex, in relaxed which the distorted protease hangs at the base of thethe serpin molecule. The primary function of inhibitory serpins mutations or dysfunction of serpins that form polymer aggregates and re-is to regu proteolytic and protect cells from nonspecific protease-mediated damage [4]. The limited extracellular presence of clade B serpins positions them to fine tune the activity of cellular protease that may have reached the extracellular compartment This delicate balance between proteases an antiproteases at the level of pancreatic islets provides important, and largely underappreciated, cues for the development and regeneration of endocrine cells in the pancreas as well as their ability to respond to inflammation
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