Journal
FRONTIERS IN CHEMISTRY
Volume 5, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2017.00013
Keywords
leishmania; deubiquitination; cysteine protease; molecular dynamic; site-directed mutagenesis; otubain
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Funding
- INCE (Institutos Nacionais de Ciencia e Tecnologia) [465771/2014-9]
- CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) - COFECUB [723/11]
- CNPq (Conselho Nacional de Ciencia e Tecnologia) [303675/2015-2, 307186/2013-0]
- FAPDF (Fundacao de Apoio a Pesquisa do Distrito Federal) [193.001.076/2015, 193.000.822/2015]
- IDEX Sorbonne Universites (SUPER)
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Deubiquitinating enzymes (DUBs) play an important role in regulating a variety of eukaryotic processes. In this context, exploring the role of deubiquitination in Leishmania infanturn could be a promising alternative to search new therapeutic targets for leishmaniasis. Here we present the first characterization of a DUB from L. infanturn, otubain (OtuLi), and its localization within parasite. The recombinant OtuLi (rOtuLi) showed improved activity on lysine 48 (K48)-linked over K63-linked tetra-ubiquitin (Ub) and site-directed mutations on amino acids close to the catalytic site (F82) or involved in Ub interaction (L265 and F182) caused structural changes as shown by molecular dynamics, resulting in a reduction or loss of enzyme activity, respectively. Furthermore, rOtuLi stimulates lipid droplet biogenesis (an inflammatory marker) and induces IL-6 and TNF-alpha secretion in peritoneal macrophages, both proinflammatory cytokines. Our findings suggest that OtuLi is a cytoplasmic enzyme with K48-linked substrate specificity that could play a part in proinflammatory response in stimulated murine macrophages.
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