Inhibition of 19S proteasome deubiquitinating activity in Schistosoma mansoni affects viability, oviposition, and structural changes

Author(s)

do Patrocinio, Andressa Barban ^[1] ; Cabral, Fernanda Janku ^[2] ; Brandao Bitencourt, Andre Luiz ^[1] ; Brigato, Olinda Mara ^[1] ; Magalhaes, Lizandra Guidi ^[3] ; de Lima Paula, Lucas Antonio ^[3] ; Franco, Larissa ^[2] ; Guerra-Sa, Renata ^[4] ; Rodrigues, Vanderlei ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto, SP - Brazil

^[2] Univ Estadual Campinas, Dept Biol Anim, Inst Biol, Campinas, SP - Brazil

^[3] Univ Franca, Nikko Pesquisa Ciencias Exatas & Tecnol, Franca, SP - Brazil

^[4] Univ Fed Ouro Preto, Nucleo Pesquisas Ciencias Biol, Ouro Preto, MG - Brazil

• Document type: Journal article
• Source: Parasitology Research; v. 119, n. 7 MAY 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 16/06769-2 - Molecular studies of deubiquitinating enzymes and its involvement in TGFb signaling pathway in the development of the reproductive system of Schistosoma mansoni
• Grantee: Vanderlei Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/07364-9 - Investigation of posttranslational histone modifications and co-regulators of expression in the Schistosoma mansoni stages
• Grantee: Fernanda Janku Cabral
• Support Opportunities: Regular Research Grants