Redundant proteolytic activation of a viral superantigen

Winslow, Gary M.; Cronin, Thomas J.; Mix, Denise; Reilly, Melissa

doi:10.1016/s0161-5890(98)00088-1

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…Recently, more conservative mutations of the putative CS2 and CSX sites have been introduced by inserting sequences naturally occurring in MMTV isolates (51). Using WT CHO cells as APCs, these authors showed that removal of the CS2 site (while keeping a WT CSX site) abolished presentation and that cell surface expression was readily detectable (51). The discrepancy between these reports proposing an essential requirement for convertase-mediated vSag processing and ours might be due to differences in the cell lines used.…”

Section: Discussionmentioning

confidence: 72%

“…This suggested that alternate proteases might contribute to the activation of vSags. Recently, more conservative mutations of the putative CS2 and CSX sites have been introduced by inserting sequences naturally occurring in MMTV isolates (51). Using WT CHO cells as APCs, these authors showed that removal of the CS2 site (while keeping a WT CSX site) abolished presentation and that cell surface expression was readily detectable (51).…”

Section: Discussionmentioning

confidence: 99%

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Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens

Denis

Shoukry

Delcourt³

et al. 2000

J Virol

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Mouse mammary tumor viruses express a superantigen essential for their life cycle. It has been proposed that viral superantigens (vSags) require processing by prohormone convertases (PCs) for activity. We now observe, using a panel of mutant forms of potential PC cleavage sites and in vitro cleavage assays, that only the CS1 (position 68 to 71) and CS2 (position 169 to 172) sites are utilized by furin and PC5. Other members of the convertase family that are expressed in lymphocytes are not endowed with this activity. Furthermore, mutant forms of two different viral superantigens, vSag7 and vSag9, which completely abrogated in vitro processing by convertases, were efficient in functional presentation to responsive T-cell hybridomas. This effect was observed in both endogenous presentation and paracrine transfer of the vSag. Processing by convertases thus appears not to be essential for vSag function. Finally, we have identified the purified endosomal protease cathepsin L as another protease that is able to cleave convertase mutant vSag in vitro, yielding fragments similar to those detected in vivo, thus suggesting that proteases other than convertases are involved in the activation of vSags.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens

Denis

Shoukry

Delcourt³

et al. 2000

J Virol

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“…The presence of different cleavage products was detected in cells and association with MHC class II molecules was detected (35)(36)(37). Evidence for a role of cleavage for superantigen function was found (38). Indirect evidence for a superantigen function of cleaved molecules came from the ability of transferring superantigens in the absence of cell contact from cell to cell (28,39,40).…”

Section: The Structure Of the Mmtv Superantigen (Orf)mentioning

confidence: 99%

Immune response to MMTV infection

Acha‐Orbea

Shakhov²,

Finke³

2007

Front Biosci

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Introduction 3. Structure, expression and transmission of the virus 4. Superantigens 5. The structure of the superantigen orf 6. Normal T-dependent immune responses 7. Live cycle of MMTV, exploiting the T cell-dependent B cell immune response 7.1. Entry of infectious MMTV in Peyer's patches 7.2. Infection of dendritic cells and B cells 7.3. Superantigen-mediated induction of helper T cells 7.4. Formation of germinal centers and long-lived memory cells 7.5. Fate of superantigen-reactive T cells 7.6. Transmission to the mammary gland 7.7. Mammary tumors 7.8. Role of the superantigen response for infection 7.9. Role of virus neutralization 8. Perspectives and conclusions 9. Acknowledgments 10. References

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“…Intercellular vSAg transfer was evidenced by the ability of the vSAg expressed in the mixed bone marrow chimeric mice to effect intrathymic deletion of reactive T cells. Evidence that vSAg-expressing CD8 T cells, which do not express class II proteins, could induce T-cell deletion in vivo also provided evidence for intercellular transfer (21). Intercellular transfer has also been demonstrated to occur in vitro by coculture of vSAg-reactive T cells with mixtures of independently transfected vSAg and class II MHC-expressing APCs (4).…”

Section: Activation Of T Cells By Mouse Mammary Tumor Virus (Mmtv) Sumentioning

confidence: 99%

Intercellular Transfer of a Soluble Viral Superantigen

Reilly

Mix

Reilly

et al. 2000

J Virol

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Mouse mammary tumor virus (MMTV) superantigens (vSAgs) can undergo intercellular transfer in vivo and in vitro such that a vSAg can be presented to T cells by major histocompatibility complex (MHC) class II proteins on antigen-presenting cells (APCs) that do not express the superantigen. This process may allow T-cell activation to occur prior to viral infection. Consistent with these findings, vSAg produced by Chinese hamster ovary (CHO) cells was readily transferred to class II IE and IA (H-2k and H-2 d ) proteins on a B-cell lymphoma or mouse splenocytes. Fixed class II-expressing acceptor cells were used to demonstrate that the vSAg, but not the class II proteins, underwent intercellular transfer, indicating that vSAg binding to class II MHC could occur directly at the cell surface. Intercellular transfer also occurred efficiently to splenocytes from endogenous retrovirus-free mice, indicating that other proviral proteins were not involved. Presentation of vSAg7 produced by a class II-negative, furin protease-deficient CHO variant (FD11) was unsuccessful, indicating that proteolytic processing was a requisite event and that proteolytic activity could not be provided by an endoprotease on the acceptor APC. Furthermore, vSAg presentation was effected using cell-free supernatant from class II-negative, vSAg-positive cells, indicating that a soluble molecule, most likely produced by proteolytic processing, was sufficient to stimulate T cells. Because the membrane-proximal endoproteolytic cleavage site in the vSAg (residues 68 to 71) was not necessary for intercellular transfer, the data support the notion that the carboxy-terminal endoproteolytic cleavage product is an active vSAg moiety. Activation of T cells by mouse mammary tumor virus (MMTV) superantigens (vSAgs) is essential for viral transmission (for a review see reference 1). This activation is mediated via interaction of the vSAgs with class II major histocompatibility complex (MHC) proteins on antigen-presenting cells (APCs) and the variable region of the ␤ chain of the T-cell receptor. The vSAgs are produced as glycosylated type II integral membrane proteins that require endoproteolytic maturation to activate T cells (11). In CHO cells, proteolytic processing is effected by furin, a member of a family of endoproteases known as protein convertases (PCs) (17), and results in the generation of one or more proteolytic products. An 18-kDa carboxy-terminal proteolytic cleavage product (p18) has been demonstrated to associate on the cell surface of B cells both with an amino-terminal vSAg proteolytic cleavage product and with the class II MHC protein IA k (23, 24). Although similar in function to the well-characterized bacterial superantigens, the vSAgs and the bacterial SAgs bear no genetic resemblance, and the structure of the vSAgs and details of their interactions with the class II MHC proteins have not been resolved.Another feature of vSAgs is their capacity to undergo intercellular transfer. vSAgs will not stimulate T cells in the absence of class II MH...

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Redundant proteolytic activation of a viral superantigen

Cited by 5 publications

References 10 publications

Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens

Alternative Proteolytic Processing of Mouse Mammary Tumor Virus Superantigens

Immune response to MMTV infection

Intercellular Transfer of a Soluble Viral Superantigen

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