Inhibition of 19S proteasome deubiquitinating activity in Schistosoma mansoni affects viability, oviposition, and struct
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HELMINTHOLOGY - ORIGINAL PAPER
Inhibition of 19S proteasome deubiquitinating activity in Schistosoma mansoni affects viability, oviposition, and structural changes Andressa Barban do Patrocinio 1 & Fernanda Janku Cabral 2 & André Luiz Brandão Bitencourt 1 & Olinda Mara Brigato 1 & Lizandra Guidi Magalhães 3 & Lucas Antônio de Lima Paula 3 & Larissa Franco 2 & Renata Guerra-Sá and 4 & Vanderlei Rodrigues 1 Received: 29 September 2019 / Accepted: 7 April 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The proteasome is the key player in the cellular protein degradation machinery and is pivotal for protein homeostasis and Schistosoma mansoni (S. mansoni) survival. Our group study provides insights into proteasome inhibitors and reveals that selective schistosomiasis agents represent an interesting branch of proteasome research linked to the development of new drugs for this neglected disease. Here, we explored the phenotypic response of S. mansoni to b-AP15, a bis-benzylidine piperidone that inhibits 26S proteasome deubiquitinases (DUBs), ubiquitin-specific protease 14 (USP14), and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5). b-AP15 induces a modest decrease in egg production in vitro and reduces viability, leading to the death of parasite couples. This inhibitor also induces a twofold increase in the accumulation of polyubiquitinated proteins in S. mansoni adult worms and causes tegument changes such as disintegration, wrinkling, and bubble formation, both throughout the length of the parasite and in the oral sucker. b-AP15 alters the cell organelles of adult S. mansoni worms, and we specifically observed mitochondrial alterations, which are suggestive of proteotoxic stress leading to autophagy. Taken together, these results indicate that the deubiquitinase function of the proteasome is essential for the parasite and support the hypothesis that the proteasome constitutes an interesting drug target for the treatment of schistosomiasis. Keywords Schistosoma mansoni . 26S proteasome . Deubiquitinating enzymes . b-AP15 inhibitor Section Editor: Xing-Quan ZHU Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00436-020-06686-4) contains supplementary material, which is available to authorized users. * Andressa Barban do Patrocinio [email protected]
Larissa Franco [email protected]
* Renata Guerra-Sá and [email protected] Fernanda Janku Cabral [email protected]
Vanderlei Rodrigues [email protected] 1
Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
2
Departamento de Biologia Animal, Instituto de Biologia, Universidade de Campinas, Campinas, São Paulo, Brasil
3
Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Franca, Brazil
4
Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Morro do Cruzeiro, Ouro Preto, MG, Brasil
André Luiz Brandão Bitencourt [email protected]
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