The neurotropic parasite is a globally distributed parasitic protozoan among mammalian hosts, including humans. During the course of infection, the CNS is the most commonly damaged organ among invaded tissues. The polymorphic rhoptry protein 18 (ROP18) is a key serine (Ser)/threonine (Thr) kinase that phosphorylates host proteins to modulate acute virulence. However, the basis of neurotropism and the specific substrates through which ROP18 exerts neuropathogenesis remain unknown. Using mass spectrometry, we performed proteomic analysis of proteins that selectively bind to active ROP18 and identified RTN1-C, an endoplasmic reticulum (ER) protein that is preferentially expressed in the CNS. We demonstrated that ROP18 is associated with the N-terminal portion of RTN1-C and specifically phosphorylates RTN1-C at Ser7/134 and Thr4/8/118. ROP18 phosphorylation of RTN1-C triggers ER stress-mediated apoptosis in neural cells. Remarkably, ROP18 phosphorylation of RTN1-C enhances glucose-regulated protein 78 (GRP78) acetylation by attenuating the activity of histone deacetylase (HDAC), and this event is associated with an increase of neural apoptosis. These results clearly demonstrate that both RTN1-C and HDACs are involved in ROP18-mediated pathogenesis of encephalitis during infection.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003310 | PMC |
| http://dx.doi.org/10.1073/pnas.1801118115 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression.
mBio
February 2023
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Toxoplasma gondii secretes various virulence effector molecules into host cells to disrupt host interferon-γ (IFN-γ)-dependent immunity. Among these effectors, ROP18 directly phosphorylates and inactivates IFN-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), leading to the subversion of IFN-inducible GTPase-induced cell-autonomous immunity. The modes of action of ROP18 have been studied extensively; however, little is known about the molecular mechanisms by which ROP18 is produced in the parasite itself.
View Article and Find Full Text PDFToxoplasma gondii ROP18 inhibits host innate immunity through cGAS-STING signaling.
FASEB J
February 2022
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, P. R. China.
Toxoplasma gondii is an opportunistic protozoan, which widely infects humans and other warm-blooded animals. The type I interferon (IFN) such as IFN-α/β is involved in cGAS-STING signaling to resist T. gondii infection.
View Article and Find Full Text PDFType-I ROP18 Targeting Human E3 Ligase TRIM21 for Immune Escape.
Front Cell Dev Biol
May 2021
Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Pathogen Biology, School of Public Health, Southern Medical University, Guangzhou, China.
is an intracellular pathogen that exerts its virulence through inhibiting host's innate immune responses, which is mainly related to the type II interferon (IFN-γ) response. IFN-γ inducible tripartite motif 21 (TRIM21), an E3 ligase, plays an important role in anti-infection responses against the intracellular pathogens including bacteria, virus, and parasite. We found that virulence factor ROP18 of the type I RH strain (ROP18) interacted with human TRIM21, and promoted the latter's phosphorylation, which subsequently accelerated TRIM21 degradation through lysosomal pathway.
View Article and Find Full Text PDFTgROP18 targets IL20RB for host-defense-related-STAT3 activation during Toxoplasma gondii infection.
Parasit Vectors
August 2020
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
Background: Toxoplasma gondii is an opportunistic protozoan infecting almost one-third of the world's population. Toxoplasma gondii rhoptry protein 18 (TgROP18) is a key virulence factor determining the parasite's acute virulence and is secreted into host cells during infection. We previously identified the interaction of TgROP18 and host cell immune-related receptor protein IL20RB, and observed the activation of STAT3 in human keratinocytes (HaCaT) cells infected by the rop16 knockout RH strain, though TgROP16 is regarded as being responsible for host STAT3 activation during T.
View Article and Find Full Text PDFDeactivation and mislocalization of Toxoplasma gondii rhoptry protein 18 induced by a single amino acid mutation on the proton transport catalytic aspartic acid.
Microbiol Res
January 2020
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28/30, CH-8006, Zurich, Switzerland.
Rhoptry protein 18 (ROP18) is a major determinant of strain-specific virulence in Toxoplasma gondii. The kinase activity of ROP18 is required for acute virulence, while the aspartate in the catalytic loop of ROP18 is considered essential for phosphoryl transfer. We showed that a single amino acid mutation at the catalytic aspartate residue (D409A mutation) significantly altered ROP18 kinase activity in vitro, and abolished ROP18-mediated ATF6β degradation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!