Post-translational modification of the myxoma-virus anti-inflammatory serpin SERP-1 by a virally encoded sialyltransferase

Nash, Piers; Barry, Michèle; Seet, Bruce T.; Veugelers, Kirstin; Hota, Susy; J, Heger; Hodgkinson, Carley; Graham, Kathryn; Jackson, Ronald J.; MCFADDEN, Grant

doi:10.1042/bj3470375

Cited by 10 publications

(13 citation statements)

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“…MYXV a-2,3-sialyltransferase contributes to post-translational modifications of the myxoma virus-encoded serpin (serineproteinase inhibitor) SERP-1 (Nash et al, 2000), a secreted viral anti-inflammatory protein. SERP-1 is the only virusencoded serpin that is secreted as a soluble glycoprotein from infected cells and it also represents the first example of a secreted virulence factor that is post-translationally modified by a virus-encoded glycosyltransferase.…”

Section: Glycosyltransferases Encoded By Poxvirusesmentioning

confidence: 99%

“…SERP-1 is the only virusencoded serpin that is secreted as a soluble glycoprotein from infected cells and it also represents the first example of a secreted virulence factor that is post-translationally modified by a virus-encoded glycosyltransferase. Even though modification of SERP-1 by the MST3N-gene product (pMST3N) is not essential for SERP-1 to inhibit protease activity in vitro (Nash et al, 2000), different hypotheses could explain the function of the sialylation of SERP-1 by pMST3N in vivo. Sialylation could decrease the antigenicity of SERP-1 or it could increase the half-life of SERP-1 within the infected tissues.…”

Section: Glycosyltransferases Encoded By Poxvirusesmentioning

confidence: 99%

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Glycosyltransferases encoded by viruses

Markine-Goriaynoff

Gillet

Etten

et al. 2004

Journal of General Virology

104

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Studies of cellular biology in recent decades have highlighted the crucial roles of glycans in numerous important biological processes, raising the concept of glycomics that is now considered as important as genomics, transcriptomics and proteomics. For millions of years, viruses have been co-evolving with their hosts. Consequently, during this co-evolution process, viruses have acquired mechanisms to mimic, hijack or sabotage host processes that favour their replication, including mechanisms to modify the glycome. The importance of the glycome in the regulation of host-virus interactions has recently led to a new concept called 'glycovirology'. One fascinating aspect of glycovirology is the study of how viruses affect the glycome. Viruses reach that goal either by regulating expression of host glycosyltransferases or by expressing their own glycosyltransferases. This review describes all virally encoded glycosyltransferases and discusses their established or putative functions. The description of these enzymes illustrates several intriguing aspects of virology and provides further support for the importance of glycomics in biological processes.

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Section: Glycosyltransferases Encoded By Poxvirusesmentioning

confidence: 99%

Section: Glycosyltransferases Encoded By Poxvirusesmentioning

confidence: 99%

Glycosyltransferases encoded by viruses

Markine-Goriaynoff

Gillet

Etten

et al. 2004

Journal of General Virology

104

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“…Myxoma virus is responsible for encoding two such serine protease modulators, Serp-1, a secreted glycoprotein that binds thrombolytic factors (tPA, uPA, and plasmin) and thrombotic factors (Factor Xa and thrombin) and Serp-2, a cross-class intracellular inhibitor that binds granzyme-B and caspase-1 (130). Serp-1 inhibits tPA, uPA, plasmin, and Factor Xa, with the exception of thrombin that requires a ten-fold molar ratio excess of Serp-1 in order for inhibition to take place.…”

Section: Viral Serpinsmentioning

confidence: 99%

“…Serp-1 inhibits tPA, uPA, plasmin, and Factor Xa, with the exception of thrombin that requires a ten-fold molar ratio excess of Serp-1 in order for inhibition to take place. Otherwise, thrombin is able cleave Serp-1 under lesser molar ratios (130)(131). Myxoma virus causes myxomatosis in old world, European rabbits producing fulminant primary and secondary lesions.…”

Section: Viral Serpinsmentioning

confidence: 99%

“…Infected rabbits typically succumb within two weeks of the initial viral infection due to immunosuppression and secondary Gram-negative bacteria infections. The duration of viral infection is characterized as a period of systematic disabling of the innate and adaptive responses in the host (130). Upon infection with Myxoma in gene knockout studies in immune competent hosts, a greater inflammatory response followed by recovery from the infection was revealed demonstrating Serp-1's profound interaction with the host inflammatory response (110,132).…”

Section: Viral Serpinsmentioning

confidence: 99%

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Serpins, the vasculature, and viral therapeutics

2006

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Serine protease inhibitors, termed serpins, are key regulators of numerous biological pathways that initiate inflammation, coagulation, angiogenesis, apoptosis, extra-cellular matrix composition and complement activation responses. Viruses have encoded serpins to guard themselves from host immune attack. The myxoma virus which infects rabbits secretes a highly potent anti-inflammatory serpin, Serp-1, which targets thrombolytic and thrombotic proteases as a means to fend off coagulation and inflammatory reactions to viral infection. These reactions act as a defense, produced by the host, to counter viral infection and invasion. When infused in animals after vascular injury, Serp-1 elicits exceptional anti-inflammatory activity, whereas the mammalian serpin, plasminogen activator inhibitor-1 (PAI-1), which also targets thrombotic and thrombolytic proteases can induce a pro-thrombotic response. During arterial injury, PAI-1 is highly expressed and increased PAI-1 concentration can result in acute thrombosis after aortic transplant in mouse models. The reactive center loop amino acid sequence is a fingerprint for serpin function and this function is highly sequence specific such that modification in this sequence can markedly alter activity. For instance, the alteration of the serpin reactive site loop P1-P1I amino acid sequence nullified the anti-inflammatory activity of Serp-1 and modification of P2-P7 initiated a pro-inflammatory response with vascular remodeling with aneurysm formation. Furthermore Serp-1 has demonstrated the capacity to utilize a mammalian serine protease receptor, the urokinase-type plasminogen activator receptor (uPAR), to alter cellular signaling in part through the actin binding protein cytoskeletal system (via filamin B). In this review, the molecular mechanisms relating inflammation and coagulation pathways to atherosclerosis and how the viral serpin, Serp-1, modifies these pathways in order to exhibit this profound anti-inflammatory activity without associated adverse thrombosis are discussed. Viral and vascular serpins targeting the thrombolytic cascade represent a potential new and untapped therapeutic resource.

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Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function

Mahon

Ambadapadi

Yaron³

et al. 2018

Biochemistry

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The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a "first-in-class" therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota. Here, we utilize a structure-guided approach to design and test a series of next-generation RCL peptides with improved therapeutic potential that is not reduced when the peptides are combined with antibiotic treatments. The crystal structure of cleaved Serp-1 was determined to 2.5 Å resolution and reveals a classical serpin structure with potential for serpin-derived RCL peptides to bind and inhibit mammalian serpins, plasminogen activator inhibitor 1 (PAI-1), anti-thrombin III (ATIII), and α-1 antitrypsin (A1AT), and target proteases. Using in silico modeling of the Serp-1 RCL peptide, S-7, we designed several modified RCL peptides that were predicted to have stronger interactions with human serpins because of the larger number of stabilizing hydrogen bonds. Two of these peptides (MPS7-8 and -9) displayed extended activity, improving survival where activity was previously lost in antibiotic-treated MHV68-infected mice (P < 0.0001). Mass spectrometry and kinetic assays suggest interaction of the peptides with ATIII, A1AT, and target proteases in mouse and human plasma. In summary, we present the next step toward the development of a promising new class of anti-inflammatory serpin-based therapeutics.

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Post-translational modification of the myxoma-virus anti-inflammatory serpin SERP-1 by a virally encoded sialyltransferase

Cited by 10 publications

References 0 publications

Glycosyltransferases encoded by viruses

Glycosyltransferases encoded by viruses

Serpins, the vasculature, and viral therapeutics

Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function

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