Dataset Information

TCP1? Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.

ABSTRACT: T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In Leishmania donovani, the ? subunit of TCP1 (LdTCP1?) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the essentiality of the LdTCP1? gene. Gene replacement studies indicated that LdTCP1? is essential for parasite survival. The LdTCP1? single-allele-replacement mutants exhibited slowed growth and decreased infectivity in mouse macrophages compared to the growth and infectivity of the wild-type parasites. Modulation of LdTCP1? expression in promastigotes also modulated cell cycle progression. Suramin, an antitrypanosomal drug, not only inhibited the luciferase refolding activity of the recombinant LdTCP1? (rLdTCP1?) homo-oligomeric complex but also exhibited potential antileishmanial efficacy both in vitro and in vivo The interaction of suramin and LdTCP1? was further validated by isothermal titration calorimetry. The study suggests LdTCP1? as a potential drug target and also provides a framework for the development of a new class of drugs.

SUBMITTER: Yadav S

PROVIDER: S-EPMC7526847 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.

Yadav Shailendra S Kuldeep Jitendra J Siddiqi Mohammad I MI Goyal Neena N

Antimicrobial agents and chemotherapy 20200722 8

T-complex protein-1 (TCP1) is a ubiquitous group II chaperonin and is known to fold various proteins, such as actin and tubulin. In <i>Leishmania donovani</i>, the γ subunit of TCP1 (LdTCP1γ) has been cloned and characterized. It forms a high-molecular-weight homo-oligomeric complex that performs ATP-dependent protein folding. In the present study, we evaluated the essentiality of the LdTCP1γ gene. Gene replacement studies indicated that LdTCP1γ is essential for parasite survival. The LdTCP1γ si ...[more]

PMID: 32457112

Similar Datasets

Project description:The importance of autophagy in parasites with a digenetic life cycle like Leishmania spp. is significant. The parasite survives as promastigotes in the insect gut and as immotile amastigotes in mammals. This study demonstrates increased autophagy in Leishmania parasite during progression of in vitro life cycle and upon exposure to stress stimuli like starvation, oxidative stress, and drugs. Autophagy inhibition during stress exposure increased cell death, indicating the importance of autophagy in cellular defense against adverse conditions. Atg8 protein, a homolog of mammalian autophagy protein LC3 is expressed in Leishmania parasite but its function remains unknown. Overexpression of Atg8 (Atg8-OE) rendered the parasites resistant to stress and capable of infecting macrophages in substantial numbers; however, disruption of the Atg8 gene (?Atg8) resulting in suppression of Atg8 protein expression, increased susceptibility to stress and reduced the capability to cause infection. A critical event in the Leishmania parasite lifecycle is the differentiation of promastigote forms to the disease causing amastigote forms. The failure of ?Atg8 parasites lacking Atg8 protein to differentiate into amastigotes, unlike the Atg8-OE and vector-transfected parasites, clearly indicated Atg8 involvement in a crucial event. The inability of ?Atg8 parasites to infect macrophages in vitro was verified in an in vivo mouse model of leishmaniases where infection could not be induced by the ?Atg8 parasites. Autophagy is known to be involved in the remodeling of damaged organelles. The accumulation of Atg8 around damaged mitochondria suggested increase of autophagy in the vicinity of the organelle. This buildup was prevented when mitochondria generated reactive oxygen species that were quenched, suggesting them as possible signaling molecules for sensing mitochondrial instability. In summary, our study provides new evidences for a crucial role of Atg8 protein in sustaining Leishmania parasite survival during life cycle and stress exposure, differentiation to amastigotes, and their infective abilities.

Dataset Information

TCP1? Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.

Publications

TCP1γ Subunit Is Indispensable for Growth and Infectivity of Leishmania donovani.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets