HDAC6 regulates antibody-dependent intracellular neutralization of viruses via deacetylation of TRIM21

Xie, Songbo; Zhang, Linlin; Dong, Dan; Ge, Ruixin; He, Qianqian; Fan, Cunxian; Xie, Wei; Zhou, Jun; Li, Dengwen; Liu, Min

doi:10.1074/jbc.ra119.011006

Cited by 21 publications

(21 citation statements)

References 40 publications

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“…TRIM21 was originally identified as an autoantigen in autoimmune diseases, including rheumatoid arthritis, Systemic lupus erythematosus, and Sjogren’s syndrome ( Schulte-Pelkum et al, 2009 ). TRIM21 acts as an important factor involved in the innate immune responses against microbial infection, including bacterial, viral, and parasite ( Hos et al, 2020 ; Mu et al, 2020 ; Xie et al, 2020 ), however, little about TRIM21 is known for parasites infection. In this study, we reported that T. gondii RH and CEP infection upregulated the expression of TRIM21, thus restricted parasite replication through NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

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

Yao

Zhou

et al. 2021

Front. Cell Dev. Biol.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yao

Zhou

et al. 2021

Front. Cell Dev. Biol.

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“…For this reason, we interrogated the transcriptome of COPS3-inactivated embryos. It is reassuring that the number of mRNAs which were perturbed by the microinjection of the sole Trim21 mRNA was very small, given the known interaction partners of TRIM21, for example, the gap-junction subunit CONNEXIN 43 48 , the tumor suppressor p53 49 or the histone deacetylase HDAC6 50 . By contrast, the transcriptome was vastly perturbed -including 'housekeeping' mRNAs -after COPS3 inactivation, and such vastness requires an explanation.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Israel

Drexler

Fuellen

et al. 2021

Preprint

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Investigations of genes required in early mammalian development are complicated by protein deposits of maternal products, which continue to operate after the gene locus has been disrupted. This leads to an underestimation of the number of genes known to be needed during the embryonic phase of cellular totipotency (up to the 4-cell stage). Here, we expose a critical role of the gene Cops3 by showing that it protects genome integrity during the 2-cell stage of mouse embryo development, in contrast to the previous functional assignment at postimplantation. This new role is mediated by a large, stable and hitherto overlooked deposit of maternal protein. Since protein abundance and stability defeat prospects of DNA- or RNA-based gene inactivation, we adopted a protein strategy of gene inactivation: antigen masking or TRIM21-mediated proteasomal degradation of COPS3. Both resulted in 2-cell embryo lethality, but the expected degradation remained outstanding, because the major fraction of the total COPS3 is secluded in a submembrane cortical rim that withstands extraction with detergent, thereby exposing a soluble vs. insoluble fraction of COPS3, which we ascribe with distinct functional properties. In mechanistic terms, transcriptomic and metabolic analyses reveal that soluble COPS3 is involved in several processes, which, however, converge on DNA endoreduplication and the accumulation of DNA strand breaks in the 2-cell nucleus, where the minor soluble fraction of COPS3 is placed. Thus, we have shown the critical role of maternal protein deposits in development, and we have also highlighted the distinction between the site of accumulation (cell cortex) and point of use (nucleus), which is a dimension of the protein-based strategies of gene inactivation not yet fully appreciated.

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“…Uncontrolled protein stability caused by aberrant ubiquitination/deubiquitination is usually associated with tumorigenesis and progression. [30][31][32] For example, loss-of-function mutation of tumor suppressor genes encoding the E3 ligase Von Hippel-Lindau syndrome, or the deubiquitylase cylindromatosis, has been implicated in several types of cancer. 16 USP21 has a dual role in tumorigenesis, largely determined by its substrate to be oncogenic or tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase‐dependent manner

Zhou

Song

Sun

et al. 2020

Asia-Pac J Clncl Oncology

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Ubiquitin-specific protease 21 (USP21) has been implicated in several types of cancer.It promotes or suppresses tumor growth in a cell-context dependent manner. Cholangiocarcinoma is a malignant tumor with a high mortality rate. However, the role of USP21 in cholangiocarcinoma remains unknown. Here, we identify that the level of USP21 is upregulated in cholangiocarcinoma using bioinformatics analysis and confirm this elevation in RBE cell lines. Cell counting and 5-ethynyl-2′-deoxyuridine incorporation assays reveal that USP21 promotes the proliferation of cholangiocarcinoma.Wound healing and transwell assays demonstrate that USP21 accelerates RBE cell migration. In addition, rescue assays reveal that reintroduction of USP21 wildtype other than the deubiquitinase-deficient C221A mutant restores USP21 depletioninduced attenuation in cell proliferation and migration, indicative of the requirement of the deubiquitinase activity. Collectively, these data indicate that USP21 is critically involved in cholangiocarcinoma tumorigenesis and may be an effective target for the treatment of cholangiocarcinoma.

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HDAC6 regulates antibody-dependent intracellular neutralization of viruses via deacetylation of TRIM21

Cited by 21 publications

References 40 publications

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

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

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase‐dependent manner

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