Endosomal proteases and antigen processing

Fineschi, Beatrice; Miller, Jim

doi:10.1016/s0968-0004(97)01116-x

Cited by 50 publications

(33 citation statements)

References 55 publications

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“…For example, cathepsin L prefers hydrophobic amino acids in P2 and basic residues in P1 (56). In contrast, cathepsin B preferentially cleaves after two basic amino acid residues in P1 and P2, but efficient cleavage still takes place if P2 consists of a hydrophobic amino acid (23). Analysis of the P4-P2= NiV F cleavage site by the software tool PEPS (Prediction of Endopeptidase Substrates [37]), which is based on known cathepsin B or cathepsin L cleavage sites in full-length protein substrates, revealed prediction scores of the NiV F cleavage site of 0.165 and 0.2 for cathepsin L and cathepsin B, respectively.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Nipah Virus Fusion Protein in MDCK Cells Is Mediated by Cathepsin B within the Endosome-Recycling Compartment

Diederich

Sauerhering

Weis

et al. 2012

J Virol

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c Proteolytic activation of the fusion protein of the highly pathogenic Nipah virus (NiV F) is a prerequisite for the production of infectious particles and for virus spread via cell-to-cell fusion. Unlike other paramyxoviral fusion proteins, functional NiV F activation requires endocytosis and pH-dependent cleavage at a monobasic cleavage site by endosomal proteases. Using prototype Vero cells, cathepsin L was previously identified to be a cleavage enzyme. Compared to Vero cells, MDCK cells showed substantially higher F cleavage rates in both NiV-infected and NiV F-transfected cells. Surprisingly, this could not be explained either by an increased F endocytosis rate or by elevated cathepsin L activities. On the contrary, MDCK cells did not display any detectable cathepsin L activity. Though we could confirm cathepsin L to be responsible for F activation in Vero cells, inhibitor studies revealed that in MDCK cells, cathepsin B was required for F-protein cleavage and productive replication of pathogenic NiV. Supporting the idea of an efficient F cleavage in early and recycling endosomes of MDCK cells, endocytosed F proteins and cathepsin B colocalized markedly with the endosomal marker proteins early endosomal antigen 1 (EEA-1), Rab4, and Rab11, while NiV F trafficking through late endosomal compartments was not needed for F activation. In summary, this study shows for the first time that endosomal cathepsin B can play a functional role in the activation of highly pathogenic NiV.

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Section: Discussionmentioning

confidence: 99%

Activation of the Nipah Virus Fusion Protein in MDCK Cells Is Mediated by Cathepsin B within the Endosome-Recycling Compartment

Diederich

Sauerhering

Weis

et al. 2012

J Virol

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“…Due to the complex nature of the cryptococcal cell wall, we reasoned that the processing requirements for liberating CnM from C. neoformans might be different from the processing requirements of peptide antigens. Proteolytic processing occurs through the actions of cathepsins, which are endosomal and lysosomal enzymes (13). These enzymes are acid-optimal proteases that belong to two major families, the aspartic acid and cysteine proteases (23).…”

Section: Discussionmentioning

confidence: 99%

Phagocytosis and Protein Processing Are Required for Presentation ofCryptococcus neoformansMitogen to T Lymphocytes

Syme

Spurrell

Ling³

et al. 2000

Infect Immun

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In addition to eliciting antigen specific T-cell-mediated immunity, Cryptococcus neoformans possesses a mitogen (CnM) that activates naive T cells to proliferate. This mechanism of T-cell activation is accessory cell dependent and major histocompatibility complex unrestricted. CnM-induced T-cell proliferation correlates with internalization of the organism, suggesting that intracellular processing is required to liberate CnM prior to presentation to T cells. To determine whether phagocytosis and processing are required, various inhibitors of accessory cell uptake and processing were used. C. neoformans was observed within the accessory cells. Paraformaldehyde fixation of the accessory cell abrogated presentation of CnM to T cells, indicating that a dynamic accessory cell surface was required. A lysosomotropic agent abrogated the response to CnM but had no effect on a control stimulus that did not require processing. Both aspartic acid and cysteine protease inhibitors blocked effective processing of CnM, so that it was unable to stimulate T cells. Finally, an inhibitor of microfilament polymerization abrogated proliferation to CnM. These results indicate that the mitogenic activity of C. neoformans requires phagocytosis of the organism, lysosomal or endosomal processing, proteolytic activity, and microfilament polymerization and intracellular transport as a prerequisite for T-cell proliferation.Cryptococcus neoformans is a pathogenic yeast that causes one of the leading fatal mycoses in AIDS (9,12,18,38). This clinical observation, in addition to animal studies, has made it clear that T-cell-mediated immunity is of paramount importance in host defense against C. neoformans (1,7,15,19,20,22,28,31). T-cell immunity is antigen specific; however, we have recently shown that T cells are also capable of responding to C. neoformans by an alternate mechanism of activation (36). Specifically, when T cells from a previously unexposed individual are placed in culture with C. neoformans, the organism induces a mitogenic response. The mitogenic T-cell response is accessory cell (AC) dependent but not major histocompatibility complex restricted (36). Since the whole organism is capable of mediating this mitogenic effect, it raises questions about how the C. neoformans mitogen (CnM) might be liberated or displayed prior to T-cell activation.We had previously shown that CnM was confined to the cell wall of the organism (32). Since CnM may be displayed on the cell wall, it is possible that it cross-links surface molecules on the T cell and AC analogous to superantigens. Alternately, the AC might produce an enzyme that results in extracellular degradation and release of CnM, with liberation of the molecule into the surrounding milieu, where it exerts its mitogenic effect. Finally, we considered the possibility that the organism must be taken up by the AC and degraded internally, with subsequent presentation of CnM by the AC to the T cell. We have previously shown that lymphocyte proliferation in response to C. neoformans correlate...

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“…Moreover, in animals, rapid uncoating after endocytosis could prevent viral antigens from being efficiently processed for presentation by MHC class II molecules, thus preventing the immune system from mounting a specific response. Indeed, the proteases involved in antigen processing for MHC class II presentation reside mostly within highly acidic compartments deep within the cell (for a review see Fineschi & Miller, 1997).…”

Section: Discussionmentioning

confidence: 99%

Mutations in the glycoprotein of viral haemorrhagic septicaemia virus that affect virulence for fish and the pH threshold for membrane fusion.

Gaudin

Kinkelin

Benmansour

1999

Journal of General Virology

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To study the molecular basis of virulence of viral haemorrhagic septicaemia virus (VHSV), we used a cross-reactive neutralizing MAb to select MAb-resistant (MAR) mutants with reduced pathogenicity for fish. From sequence determination of the G gene of MAR mutants, attenuated laboratory variant and avirulent field strains, we identified two distant regions of the glycoprotein associated with virulence : region I (aa 135-161), homologous to the putative fusion peptide of both rabies virus (RV) and vesicular stomatitis virus (VSV), and region II (surrounding aa 431-433), homologous to RV and VSV domains controlling the conformational changes necessary for the fusion process to take place. Simultaneous mutations in both regions resulted in the most attenuated phenotype and we obtained genetic evidence that regions I and II may be structurally linked. As the MAR mutants had mutations in or near domains involved in fusion, the fusion properties of VHSV and its variants were analysed. This work allowed us to postulate that the fusion domain of VHSV is probably constituted of two distinct regions of the protein connected through a disulfide bridge between cysteines 110 and 152. Finally, we obtained evidence suggesting that the pH threshold for fusion is a determinant for virulence : restriction of fusion to a more acidic pH was associated with attenuation for the variant tr25 which had a shift of the threshold for maximal fusion from pH 6n30 (for the parental strain) to pH 6n00 ; conversely, two field strains which had maximal fusion at pH 6n60 were the most virulent.

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Endosomal proteases and antigen processing

Cited by 50 publications

References 55 publications

Activation of the Nipah Virus Fusion Protein in MDCK Cells Is Mediated by Cathepsin B within the Endosome-Recycling Compartment

Activation of the Nipah Virus Fusion Protein in MDCK Cells Is Mediated by Cathepsin B within the Endosome-Recycling Compartment

Phagocytosis and Protein Processing Are Required for Presentation ofCryptococcus neoformansMitogen to T Lymphocytes

Mutations in the glycoprotein of viral haemorrhagic septicaemia virus that affect virulence for fish and the pH threshold for membrane fusion.

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