Human clade B serpins (ov-serpins) belong to a cohort of evolutionarily dispersed intracellular proteinase inhibitor clades that protect cells from promiscuous proteolysis

Abstract

Serpins are unique among the various types of active site proteinase inhibitors because they covalently trap their targets by undergoing an irreversible conformational rearrangement. Members of the serpin superfamily are present in the three major domains of life (Bacteria, Archaea and Eukarya) as well as several eukaryotic viruses. The human genome encodes for at least 35 members that segregate evolutionarily into nine (A-I) distinct clades. Most of the human serpins are secreted and circulate in the bloodstream where they reside at critical checkpoints intersecting self-perpetuating proteolytic cascades such as those of the clotting, thrombolytic and complement systems. Unlike these circulating serpins, the clade B serpins (ov-serpins) lack signal peptides and reside primarily within cells. Most of the human clade B serpins inhibit serine and/or papain-like cysteine proteinases and protect cells from exogenous and endogenous proteinase-mediated injury. Moreover, as sequencing projects expand to the genomes of other species, it has become apparent that intracellular serpins belonging to distinct phylogenic clades are also present in the three major domains of life. As some of these serpins also guard cells against the deleterious effects of promiscuous proteolytic activity, we propose that this cytoprotective function, along with similarities in structure are common features of a cohort of intracellular serpin clades from a wide variety of species.

Control of granzymes by serpins

“…The 12 remaining clades are composed of animal serpins, with a single, species-based clade each for nematode, fluke and horseshoe crab serpins, whereas the nine clades (clades A-I) present in higher animals segregate on the basis of function, rather than species. Eight of the nine mammalian clades comprise extracellular proteins, whereas clade B serpins are predominantly intracellular and, by definition, lack classical N-terminal secretion signals, 18 although some members are secreted under specific circumstances (reviewed by Silverman et al 19 ).…”

“…19,44 Specifically, it has been shown that SERPINB9 is localised in the nucleus and cytoplasm of cells, 45 it can prevent gzmB-mediated cell death 46 and associates with the cytoplasmic face of gzmB-containing granules in CLs attacking target cells. 24 In resting CL, SERPINB9 is highly expressed, whereas the gzmB protein is low or undetectable, 24 ensuring their survival.…”

Anti-serpin Antibody-mediated Regulation of Proteases in Autoimmune Diabetes

“…Proteases can also influence many other processes, including tissue remodeling and resolution of inflammation (3,4), suggesting that their activity is not always pathogenic. Given the critical role of protease activity during formation of autoimmune inflammation (2,5,6), it is not surprising that proteases are modulated by a number of inhibitors, including B clade molecules, also known as ov-serpins (7,8). The inhibitory activity of these serpins may in turn be regulated.…”

SERPINB11 Is a New Noninhibitory Intracellular Serpin

“…Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental 4 The abbreviations used are: RSL, reactive site loop; SI, stoichiometry of inhibition; SNP, single nucleotide polymorphism; s4B and s5B, strand 4B and 5B, respectively; hA, hB, hD, and hI, helix A, B, D, E, and I, respectively; contig, group of overlapping clones; GST, glutathione S-transferase; pNA, p-nitroanilide; PBS, phosphate-buffered saline; MALDI-MS, matrix-assisted laser desorption ionization mass spectroscopy; serpin; serine peptidase inhibitor; 4-NA, 4-nitroanalide. …”