Toxoplasma gondii Type-I ROP18 Targeting Human E3 Ligase TRIM21 for Immune Escape

Abstract

Toxoplasma gondii 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 T. gondii virulence factor ROP18 of the type I RH strain (TgROP18I) interacted with human TRIM21, and promoted the latter’s phosphorylation, which subsequently accelerated TRIM21 degradation through lysosomal pathway. Furthermore, TRIM21 protein level was found to be upregulated during RH and CEP strains of T. gondii infection. TRIM21 knocking down reduced the ubiquitin labeling on the parasitophorous vacuole membrane (PVM) [which led to parasitophorous vacuole (PV) acidification and death of CEP tachyzoites], and relieved the inhibition of CEP proliferation induced by IFN-γ in human foreskin fibroblast (HFF) cells which was consistent with the result of TRIM21 overexpression. On the other hand, TRIM21 overexpression enhanced the inhibition of CEP proliferation, and inhibited the binding of IκB-α with p65 to activate the IFN-γ-inducible NF-κB pathway, which might be resulted by TRIM21-IκB-α interaction. In brief, our research identified that in human cells, IFN-γ-inducible TRIM21 functioned in the innate immune responses against type III T. gondii infection; however, TgROP18I promoted TRIM21 phosphorylation, leading to TRIM21 degradation for immune escape in type I strain infection.

The Role of Hormones and Toxoplasma gondii Infection to Change the Secondary Sex Ratio

“…The immune changes that occur after infection may have a role in determining the fetus gender or stimulating and protecting specific gender, thus increasing SSR. Immunosuppressive is one of the phenomenons in toxoplasmosis infection, Where the infection decreases NK cells, white cells and monocytes [34,35], which gives the greatest opportunity for male fetuses to develop, especially since they have the Y production on their surface. It was found that the male fetus is 1.62 times more than the female fetus is developing in the womb [31].…”

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles

“…However, PV ubiquitylation is only moderately reduced in Trim21-deficient mouse cells, and the defect is limited to polyubiquitin chains linked at lysine residue 63 (K63) ( 38 ). TRIM21 also facilitates PV ubiquitylation in human fibroblasts infected with an avirulent type III strain of Toxoplasma but not in cells infected with a virulent type II strain that expresses high levels of the secreted virulence factor ROP18, a kinase targeting TRIM21 for lysosomal degradation ( 39 – 41 ).…”

A heterotrimeric complex ofToxoplasmaproteins promotes parasite survival in interferon gamma stimulated human cells

“…In mouse embryonic fibroblasts (MEFs) and bone marrow-derived macrophages (BMDMs), TRAF6-mediated ubiquitination of type II and III vacuoles enhances the recruitment of GBPs, resulting in rupture of the PVM (Haldar et al ., 2015; Mukhopadhyay et al ., 2020). The E3 ligase TRIM21 has also been shown to promote clearance of type II and III strains in vivo (Foltz et al ., 2017), and ubiquitinates type III vacuoles in human foreskin fibroblasts (HFFs) resulting in parasite growth restriction (Yao et al ., 2021). In human umbilical vein endothelial cells (HUVECs), K63-linked ubiquitination initiates a cascade of autophagy marker recruitment that culminates in acidification of the parasite vacuole (Clough et al ., 2016), while in HeLa cells ubiquitination instead leads to recruitment of LC3 and stunting of parasite growth (Selleck et al ., 2015).…”