TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy

Liu, Tao; Tang, Qin; Liu, Kunpeng; Xie, Weidong; Liu, Xin; Wang, Huishan; Wang, Rong Fu; Cui, Jun

doi:10.1016/j.celrep.2016.07.019

Cited by 140 publications

(101 citation statements)

References 39 publications

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“…The stability of AIM2 protein can be modulated by infection with Pseudomonas aeruginosa in macrophages (Pang et al ., 2015). Knockdown of TRIM11 led to a pro‐longed half‐life of exogenous AIM2 in 293T cells (Liu et al ., 2016). These data may provide a post‐translational mechanism that bridges virus infection and tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

Chen

Liu

et al. 2017

Molecular Oncology

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Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis.

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Section: Discussionmentioning

confidence: 99%

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

Chen

Liu

et al. 2017

Molecular Oncology

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“…The importance of TRIM11 was first reported in nervous system function, such as in Alzheimer's disease, dopamine beta-hydroxylase expression, Pax6-dependent neurogenesis and neuron cell survival [9][10][11][12]. TRIM11 was also found to be important in IFNβ production and antiviral activity, restricting HIV-1 replication and autophagy [13][14][15]. Di and colleagues found overexpression of TRIM11 in high-grade gliomas and demonstrated that TRIM11 has an oncogenic function mediated through the epidermal growth factor receptor (EGFR) signaling pathway [16].…”

Section: Introductionmentioning

confidence: 99%

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Liu

Rao

Lou

et al. 2017

Cell Physiol Biochem

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Background/Aims: The tripartite motif containing (TRIM) family plays crucial roles in tumor development and progression. However, little is known about the function and mechanism of TRIM11 in hepatocellular carcinoma (HCC). Methods: The expression levels of TRIM11 were examined by real-time PCR, Western blot and Immunohistochemical (IHC) staining. TRIM11 knockdown cells were produced by lentivirus infection, and functional assays, such as MTT, colony formation assay, migration and invasion assays and a xenograft tumor model were used to investigate the role of TRIM11 in HCC. We also determined the effect of TRIM11 on p53 signaling and its downstream molecules. Results: We found that TRIM11 mRNA and protein levels were significantly increased in HCC tissues as compared with normal tissues; increased levels correlated with poor patient survival. By loss-and gain-of-function investigations, knockdown of TRIM11 suppressed cell proliferation, migration, invasion in vitro and tumor growth in vivo. Moreover, TRIM11 negatively regulated p53 expression. Knockdown of p53 abrogated the in vitro and in vivo biological functions of TRIM11 shRNA in HCC cells. Conclusions: These data show that TRIM11 exerts its oncogenic effect in HCC by downregulating p53 both in vitro and in vivo. Our data provide new insights into the pathogenesis of HCC and indicate that TRIM11 may serve as a new therapeutic target for HCC treatment.

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“…Both pharmacological inhibition of autophagy and loss of p62 can greatly increase activation of caspase-1 and inflammatory cytokine production in response to AIM2 inducer poly(dA:dT) in monocytes (31). AIM2 can also undergo ubiquitination and be degraded by p62-dependent selective autophagy in macrophages upon poly(dA:dT) treatment (32). Tripartite motif 11, an E3 ubiquitin ligase, was shown to associate with AIM2 and facilitate its recruitment to p62 for autophagic degradation (32,33).…”

Section: Inflammasome Regulation Of Autophagymentioning

confidence: 99%

“…AIM2 can also undergo ubiquitination and be degraded by p62-dependent selective autophagy in macrophages upon poly(dA:dT) treatment (32). Tripartite motif 11, an E3 ubiquitin ligase, was shown to associate with AIM2 and facilitate its recruitment to p62 for autophagic degradation (32,33). Supporting this notion of ubiquitination of inflammasome resulting in degradation as a form of regulation, TRIM20 was also shown in a separate study to target a group of inflammasome components for autophagic degradation in macrophages, including NLRP3, NLRP1 and pro-caspase-1 in response to IFN-γ stimulation (34).…”

Section: Inflammasome Regulation Of Autophagymentioning

confidence: 99%

Inflammasome and Autophagy Regulation: A Two-way Street

Sun

Fan

Billiar

et al. 2017

Mol Med

159

125

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Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer's disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases.

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TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy

Cited by 140 publications

References 39 publications

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Inflammasome and Autophagy Regulation: A Two-way Street

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