Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F23%3A00580493" target="_blank" >RIV/60077344:_____/23:00580493 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/61388963:_____/23:00580493 RIV/60076658:12310/23:43906690
Výsledek na webu
<a href="https://link.springer.com/article/10.1007/s00018-023-04993-4" target="_blank" >https://link.springer.com/article/10.1007/s00018-023-04993-4</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1007/s00018-023-04993-4" target="_blank" >10.1007/s00018-023-04993-4</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host
Popis výsledku v původním jazyce
Tick saliva injected into the vertebrate host contains bioactive anti-proteolytic proteins from the cystatin family, however, the molecular basis of their unusual biochemical and physiological properties, distinct from those of host homologs, is unknown. Here, we present Ricistatin, a novel secreted cystatin identified in the salivary gland transcriptome of Ixodes ricinus ticks. Recombinant Ricistatin inhibited host-derived cysteine cathepsins and preferentially targeted endopeptidases, while having only limited impact on proteolysis driven by exopeptidases. Determination of the crystal structure of Ricistatin in complex with a cysteine cathepsin together with characterization of structural determinants in the Ricistatin binding site explained its restricted specificity. Furthermore, Ricistatin was potently immunosuppressive and anti-inflammatory, reducing levels of pro-inflammatory cytokines IL-6, IL-1 beta, and TNF-alpha and nitric oxide in macrophages, IL-2 and IL-9 levels in Th9 cells, and OVA antigen-induced CD4(+) T cell proliferation and neutrophil migration. This work highlights the immunotherapeutic potential of Ricistatin and, for the first time, provides structural insights into the unique narrow selectivity of tick salivary cystatins determining their bioactivity.
Název v anglickém jazyce
Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host
Popis výsledku anglicky
Tick saliva injected into the vertebrate host contains bioactive anti-proteolytic proteins from the cystatin family, however, the molecular basis of their unusual biochemical and physiological properties, distinct from those of host homologs, is unknown. Here, we present Ricistatin, a novel secreted cystatin identified in the salivary gland transcriptome of Ixodes ricinus ticks. Recombinant Ricistatin inhibited host-derived cysteine cathepsins and preferentially targeted endopeptidases, while having only limited impact on proteolysis driven by exopeptidases. Determination of the crystal structure of Ricistatin in complex with a cysteine cathepsin together with characterization of structural determinants in the Ricistatin binding site explained its restricted specificity. Furthermore, Ricistatin was potently immunosuppressive and anti-inflammatory, reducing levels of pro-inflammatory cytokines IL-6, IL-1 beta, and TNF-alpha and nitric oxide in macrophages, IL-2 and IL-9 levels in Th9 cells, and OVA antigen-induced CD4(+) T cell proliferation and neutrophil migration. This work highlights the immunotherapeutic potential of Ricistatin and, for the first time, provides structural insights into the unique narrow selectivity of tick salivary cystatins determining their bioactivity.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10608 - Biochemistry and molecular biology
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2023
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Cellular and Molecular Life Sciences
ISSN
1420-682X
e-ISSN
1420-9071
Svazek periodika
80
Číslo periodika v rámci svazku
11
Stát vydavatele periodika
CH - Švýcarská konfederace
Počet stran výsledku
17
Strana od-do
339
Kód UT WoS článku
001093315500001
EID výsledku v databázi Scopus
2-s2.0-85174918368