Control of granzymes by serpins

Abstract

Although proteolysis mediated by granzymes has an important role in the immune response to infection or tumours, unrestrained granzyme activity may damage normal cells. In this review, we discuss the role of serpins within the immune system, as specific regulators of granzymes. The well-characterised human granzyme B-SERPINB9 interaction highlights the cytoprotective function that serpins have in safeguarding lymphocytes from granzymes that may leak from granules. We also discuss some of the pitfalls inherent in using rodent models of granzyme-serpin interactions and the ways in which our understanding of serpins can help resolve some of the current, contentious issues in granzyme biology. Cell Death and Differentiation (2010) 17, 586-595; doi:10.1038/cdd.2009; published online 6 November 2009As described elsewhere in this series, granzymes are key mediators of cytotoxic lymphocyte (CL) function, exhibiting both intracellular and extracellular functions. Thus, it is imperative that their activities be tightly controlled. Too little activity reduces the effectiveness of the immune system, resulting in infection and cancer. Conversely, overactivity can lead to disease caused by tissue destruction and cellular apoptosis. This review focusses on the manner in which granzyme activity is controlled at the posttranslational level by members of the serpin superfamily.The serpin superfamily is an ever-expanding group of structurally related proteins, currently comprising approximately 1000 members across all kingdoms of life. 1,2 Serpins function as intracellular or extracellular regulators of a wide range of physiological processes such as complement activation, blood coagulation and apoptosis. Within the vertebrate immune system, they control proteases of the classical and innate complement systems, and are also potent inhibitors of many leukocyte granule proteases. Serpin StructureStructures of almost 100 serpins from viruses to humans have been determined and all conform to the same basic architecture first described in 1984. The fold comprises nine a-helices, three b-sheets and a variable reactive centre loop (RCL), which is the primary site of interaction with target proteases (Figure 1a). The first structure determined was human SERPINA1 cleaved within the RCL. 3 Surprisingly, it was found that the residues around the cleavage point were separated by almost 70 Å , with the N-terminal portion of the RCL inserted into b-sheet A to form a fully antiparallel sixstranded sheet. It has subsequently been shown that, in the native state, the RCL is solvent exposed, and that its insertion into b-sheet A is a consequence of the inhibitory mechanism. The RCL is flanked by two highly conserved motifs (the proximal and distal hinges) that permit its insertion into b-sheet A. Insertion is also facilitated by the breach and shutter regions that assist the opening of b-sheet A and by the movement of helix F. 4 The RCL is a critical determinant of serpin inhibitory specificity, acting as a pseudosubstrate and cleavage site for the...

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“…43 Serpin Family C Member 1 (SERPINC1), also known as Antithrombin III, is a known inhibitor of T cell-derived Granzyme A. 44,45 The reproducible PID-enriched amplification of these genes suggests the possibility that amplification of one or more of these genes, alone or in combination, may play a functional role in immune escape that contributes to the immunologically cold phenotype of the PID immune subclass.…”

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“…In vivo, the catalytic activity of Grs and other serine proteases is inhibited by serine protease inhibitors or serpins (81). Inhibition occurs through proteolytic attack of the serpin by the Grs, after which a covalent bond is formed between the serpin and the active site of Gr (81). Enzyme/serpin complexes are subsequently removed from the circulation by the liver.…”

“…Another question is whether extracellular circulating Grs are active, or whether their activity is reduced due to binding by protease inhibitors. In vivo, the catalytic activity of Grs and other serine proteases is inhibited by serine protease inhibitors or serpins (81). Inhibition occurs through proteolytic attack of the serpin by the Grs, after which a covalent bond is formed between the serpin and the active site of Gr (81).…”

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“…As discussed in the review by Kaiserman and Bird, 10 although inhibitors have been identified for some granzymes, surprisingly little is known pertaining to any pathophysiological role for granzyme serine protease inhibitors (serpins) in disease. Much research needs to be done to verify whether they inhibit granzymes in vivo and whether alterations in their regulation, levels, and/or activity are altered in disease.…”