Title |
Revealing a Novel Otubain-Like Enzyme from Leishmania infantum with Deubiquitinating Activity toward K48-Linked Substrate
|
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Published in |
Frontiers in Chemistry, March 2017
|
DOI | 10.3389/fchem.2017.00013 |
Pubmed ID | |
Authors |
Clênia S. Azevedo, Bruna C. Guido, Jhonata L. Pereira, Diego O. Nolasco, Rafael Corrêa, Kelly G. Magalhães, Flávia N. Motta, Jaime M. Santana, Philippe Grellier, Izabela M. D. Bastos |
Abstract |
Deubiquitinating enzymes (DUBs) play an important role in regulating a variety of eukaryotic processes. In this context, exploring the role of deubiquitination in Leishmania infantum could be a promising alternative to search new therapeutic targets for leishmaniasis. Here we present the first characterization of a DUB from L. infantum, 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-α 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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