A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

The authors gratefully thank Marion Müller, Christiane Palissa, Yvonne Weber, Bettina Sonnenburg, and Beate Anders for the excellent technical assistance and Franziska Rohr for her help within the animal facility. We also thank Prof. Judith E. Allen for her expertise, critical advice, and intellectual discussion of the topic.Peer reviewe

A Helminth Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

Immunomodulation of airway hyperreactivity by excretory secretory ES products of the first larval stage L1 of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELM amp; 945; interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts own chitinase activity in the inflamed lung. The three dimensional structure of the T. suis chitinase as determined by high resolution X ray crystallography revealed high similarities to mouse acidic mammalian chitinase AMCase but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease ameliorating effect of the helminth derived chitinase on allergic lung inflammatio

Proteasomes generate spliced epitopes by two different mechanisms and as efficiently as non-spliced epitopes

Proteasome-catalyzed peptide splicing represents an additional catalytic activity of proteasomes contributing to the pool of MHC-class I-presented epitopes. We here biochemically and functionally characterized a new melanoma gp100 derived spliced epitope. We demonstrate that the gp100mel47–52/40–42 antigenic peptide is generated in vitro and in cellulo by a not yet described proteasomal condensation reaction. gp100mel47–52/40–42 generation is enhanced in the presence of the β5i/LMP7 proteasome-subunit and elicits a peptide- specific CD8+ T cell response. Importantly, we demonstrate that different gp100mel-derived spliced epitopes are generated and presented to CD8+ T cells with efficacies comparable to non-spliced canonical tumor epitopes and that gp100mel-derived spliced epitopes trigger activation of CD8+ T cells found in peripheral blood of half of the melanoma patients tested. Our data suggest that both transpeptidation and condensation reactions contribute to the frequent generation of spliced epitopes also in vivo and that their immune relevance may be comparable to non-spliced epitopes

Solar Radiation Maps

[EN]Solar maps are very interesting tools to describe the characteristics of a region from the solar radiation point of view, and can be applied in atmospheric sciences and for energy engineering. To make them possible, a solar radiation numerical model is proposed. This one allows us to estimate radiation values on any point on earth. The model takes into account the terrain surface conditions and the cast shadows. The procedure uses 2-D adaptive triangles meshes built refining according to surface and albedo characteristics. Solar irradiance values are obtained for clear sky conditions. Using clear sky index as a conversion factor, real sky values are computed in terms of irradiance or irradiation with a desired time step. Finally, the solar radiation maps are obtained for all the domain

A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

From Hindawi via Jisc Publications RouterHistory: publication-year 2021, received 2021-09-02, accepted 2021-10-25, pub-print 2021-11-25, archival-date 2021-11-25Publication status: PublishedFunder: Coronado BiosciencesFunder: FAZIT Stiftung; doi: http://dx.doi.org/10.13039/501100003099Funder: Deutsche Forschungsgemeinschaft; doi: http://dx.doi.org/10.13039/501100001659; Grant(s): GRK 1673Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts’ own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation

A single amino acid residue regulates PTEN-binding and stability of the Spinal Muscular Atrophy protein SMN

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA

The N-terminal domain of Tob55 has a receptor-like function in the biogenesis of mitochondrial beta-barrel proteins

β-Barrel proteins constitute a distinct class of mitochondrial outer membrane proteins. For import into mitochondria, their precursor forms engage the TOM complex. They are then relayed to the TOB complex, which mediates their insertion into the outer membrane. We studied the structure–function relationships of the core component of the TOB complex, Tob55. Tob55 precursors with deletions in the N-terminal domain were not affected in their targeting to and insertion into the mitochondrial outer membrane. Replacement of wild-type Tob55 by these deletion variants resulted in reduced growth of cells, and mitochondria isolated from such cells were impaired in their capacity to import β-barrel precursors. The purified N-terminal domain was able to bind β-barrel precursors in a specific manner. Collectively, these results demonstrate that the N-terminal domain of Tob55 recognizes precursors of β-barrel proteins. This recognition may contribute to the coupling of the translocation of β-barrel precursors across the TOM complex to their interaction with the TOB complex