-
Seminars in Cell & Developmental Biology Feb 2017Serpins are the largest known family of serine proteinase inhibitors and perform a variety of physiological functions in arthropods. Herein, we review the field of... (Review)
Review
Serpins are the largest known family of serine proteinase inhibitors and perform a variety of physiological functions in arthropods. Herein, we review the field of serpins in arthropod biology, providing an overview of current knowledge and topics of interest. Serpins regulate insect innate immunity via inhibition of serine proteinase cascades that initiate immune responses such as melanization and antimicrobial peptide production. In addition, several serpins with anti-pathogen activity are expressed as acute-phase serpins in insects upon infection. Parasitoid wasps can downregulate host serpin expression to modulate the host immune system. In addition, examples of serpin activity in development and reproduction in Drosophila have also been discovered. Serpins also function in host-pathogen interactions beyond immunity as constituents of venom in parasitoid wasps and saliva of blood-feeding ticks and mosquitoes. These serpins have distinct effects on immunosuppression and anticoagulation and are of interest for vaccine development. Lastly, the known structures of arthropod serpins are discussed, which represent the serpin inhibitory mechanism and provide a detailed overview of the process.
Topics: Alternative Splicing; Animals; Arthropods; Host-Pathogen Interactions; Immunity; Reproduction; Serpins
PubMed: 27603121
DOI: 10.1016/j.semcdb.2016.09.001 -
International Journal of Molecular... Jun 2021Inflammatory bowel diseases (IBD) are incurable disorders whose prevalence and global socioeconomic impact are increasing. While the role of host genetics and immunity... (Review)
Review
Inflammatory bowel diseases (IBD) are incurable disorders whose prevalence and global socioeconomic impact are increasing. While the role of host genetics and immunity is well documented, that of gut microbiota dysbiosis is increasingly being studied. However, the molecular basis of the dialogue between the gut microbiota and the host remains poorly understood. Increased activity of serine proteases is demonstrated in IBD patients and may contribute to the onset and the maintenance of the disease. The intestinal proteolytic balance is the result of an equilibrium between the proteases and their corresponding inhibitors. Interestingly, the serine protease inhibitors (serpins) encoded by the host are well reported; in contrast, those from the gut microbiota remain poorly studied. In this review, we provide a concise analysis of the roles of serine protease in IBD physiopathology and we focus on the serpins from the gut microbiota (gut serpinome) and their relevance as a promising therapeutic approach.
Topics: Animals; Gastrointestinal Microbiome; Humans; Inflammatory Bowel Diseases; Serine Proteases; Serpins
PubMed: 34200095
DOI: 10.3390/ijms22116088 -
Aging Sep 2021
Topics: Aging; Alzheimer Disease; Glioblastoma; Humans; Serpins
PubMed: 34587119
DOI: 10.18632/aging.203603 -
Journal of Thrombosis and Haemostasis :... Dec 2020Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and... (Review)
Review
Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and extrinsic pathways. Two important structural features that participate in the regulatory function of AT include a mobile reactive center loop that binds to active site of coagulation proteases, trapping them in the form of inactive covalent complexes, and a basic D-helix that binds to therapeutic heparins and heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The binding of D-helix of AT by therapeutic heparins promotes the reactivity of the serpin with coagulation proteases by several orders of magnitude by both a conformational activation of the serpin and a template (bridging) mechanism. In addition to its essential anticoagulant function, AT elicits a potent anti-inflammatory signaling response when it binds to distinct vascular endothelial cell HSPGs, thereby inducing prostacyclin synthesis. Syndecans-4 has been found as a specific membrane-bound HSPG receptor on endothelial cells that relays the signaling effect of AT to the relevant second messenger molecules in the signal transduction pathways inside the cell. However, following cleavage by coagulation proteases and/or by spontaneous conversion to a latent form, AT loses both its anti-inflammatory activity and high-affinity interaction with heparin and HSPGs. Interestingly, these low-affinity heparin conformers of AT elicit potent proapoptotic and antiangiogenic activities by also binding to specific HSPGs by unknown mechanisms. This review article will summarize current knowledge about mechanisms through which different conformers of AT exert their serine protease inhibitory and intracellular signaling functions in these biological pathways.
Topics: Anticoagulants; Antithrombin III; Antithrombins; Endothelial Cells; Heparin; Signal Transduction
PubMed: 32780936
DOI: 10.1111/jth.15052 -
The American Journal of Pathology Jul 2015
Topics: Animals; Eye Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Melanoma; Microphthalmia-Associated Transcription Factor; Nerve Growth Factors; Serpins; Skin Neoplasms
PubMed: 26093987
DOI: 10.1016/j.ajpath.2015.05.002 -
International Journal of Molecular... Dec 2020Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to... (Review)
Review
Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.
Topics: Animals; Biomarkers; Disease Susceptibility; Glycosylation; Humans; Ligands; Oxidation-Reduction; Peptides; Protein Binding; Protein Multimerization; Protein Processing, Post-Translational; Proteolysis; Structure-Activity Relationship; alpha 1-Antitrypsin
PubMed: 33276468
DOI: 10.3390/ijms21239187 -
Biochemical Society Transactions Apr 2021Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to... (Review)
Review
Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders - collectively termed the 'serpinopathies' - but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by 'omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues - as well as their dysregulation in OA - are explored.
Topics: Animals; Cartilage; Extracellular Matrix; Gene Expression Regulation; Humans; Metalloproteases; Multigene Family; Osteoarthritis; Protein Conformation; Serpins
PubMed: 33843993
DOI: 10.1042/BST20201231 -
Cellular and Molecular Life Sciences :... Oct 2021Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30... (Review)
Review
Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.
Topics: Animals; Axons; Epilepsies, Myoclonic; Heredodegenerative Disorders, Nervous System; Humans; Neurodegenerative Diseases; Neurons; Neuropeptides; Polymerization; Serpins; Neuroserpin
PubMed: 34405255
DOI: 10.1007/s00018-021-03907-6 -
Journal For Immunotherapy of Cancer Mar 2023Initial clinical responses with gene engineered chimeric antigen receptor (CAR) T cells in cancer patients are highly encouraging; however, primary resistance and also...
BACKGROUND
Initial clinical responses with gene engineered chimeric antigen receptor (CAR) T cells in cancer patients are highly encouraging; however, primary resistance and also relapse may prevent durable remission in a substantial part of the patients. One of the underlying causes is the resistance mechanisms in cancer cells that limit effective killing by CAR T cells. CAR T cells exert their cytotoxic function through secretion of granzymes and perforin. Inhibition of granzyme B (GrB) can underlie resistance to T cell-mediated killing, and it has been shown that serine proteinase inhibitor serpin B9 can effectively inhibit GrB. We aimed to determine whether expression of serpin B9 by cancer cells can lead to resistance toward CAR T cells.
METHODS
Serpin B9 gene and protein expression were examined by R2 or DepMap database mining and by western blot or flow cytometric analysis, respectively. Coculture killing experiments were performed with melanoma cell line MeWo, diffuse large B cell lymphoma (DLBCL) cell line OCI-Ly7 or primary chronic lymphocytic leukemia (CLL) cells as target cells and natural killer cell line YT-Indy, CD20 CAR T cells or CD19 CAR T cells as effector cells and analyzed by flow cytometry.
RESULTS
Serpin B9 protein expression was previously shown to be associated with clinical outcome in melanoma patients and in line with these observations we demonstrate that enforced serpin B9 expression in melanoma cells reduces sensitivity to GrB-mediated killing. Next, we examined serpin B9 expression in a wide array of primary tumor tissues and human cell lines to find that serpin B9 is uniformly expressed in B-cell lymphomas and most prominently in DLBCL and CLL. Subsequently, using small interfering RNA, we silenced serpin B9 expression in DLBCL cells, which increased their sensitivity to CD20 CAR T cell-mediated killing. In addition, we showed that co-ulture of primary CLL cells with CD20 CAR T cells results in selection of serpin B9-high CLL cells, suggesting these cells resist CAR T-cell killing.
CONCLUSIONS
Overall, the data indicate that serpin B9 is a resistance mediator for CAR T cell-mediated tumor cell killing that should be inhibited or bypassed to improve CAR T-cell responses.
Topics: Humans; Cell Death; Cytotoxicity, Immunologic; Leukemia, Lymphocytic, Chronic, B-Cell; Serpins; T-Lymphocytes
PubMed: 36931661
DOI: 10.1136/jitc-2022-006364 -
Seminars in Cell & Developmental Biology Feb 2017The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the... (Review)
Review
The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure.
Topics: Allosteric Regulation; Animals; Biological Transport; Hormones; Humans; Models, Molecular; Serpins
PubMed: 28027946
DOI: 10.1016/j.semcdb.2016.12.007