Tripartite Motif 24 (Trim24/Tif1α) Tumor Suppressor Protein Is a Novel Negative Regulator of Interferon (IFN)/Signal Transducers and Activators of Transcription (STAT) Signaling Pathway Acting through Retinoic Acid Receptor α (Rarα) Inhibition

Tisserand, Johan; Khetchoumian, Konstantin; Thibault, Christelle; Dembélé, Doulaye; Chambon, Pierre; Losson, Régine

doi:10.1074/jbc.m111.225680

Cited by 67 publications

(58 citation statements)

References 55 publications

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“…Interestingly, GFI1 suppression in macrophages results in an exaggerated production of inflammatory cytokines following LPS stimulation (20). In addition, TRIM24 knockout (KO) mice have an overactivation of the IFN/STAT pathway (45). Inhibition of both TRIM24 and GFI1 could therefore have important inflammatory consequences in MA-CA/04-infected mice.…”

Section: Discussionmentioning

confidence: 99%

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Josset

Belser

Pantin‐Jackwood

et al. 2012

J Virol

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Section: Discussionmentioning

confidence: 99%

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Josset

Belser

Pantin‐Jackwood

et al. 2012

J Virol

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“…The Tripartite motif (TRIM) protein family is defined by conserved N-terminal domains of RING, B- box and coiled-coil and variable C-terminal domains, which contribute to TRIM protein functions in differentiation, development, oncogenesis and apoptosis [3]. TRIM24 (previously known as TIF1α) is a multi-functional protein: an E3-ubiquitin ligase targeting p53 for degradation, a co-regulator of nuclear receptors, and a Plant Homeodomain (PHD)/Bromodomain histone “reader” [4–7]. TRIM24 is highly expressed in multiple types of human cancers, including breast [5, 6], head and neck [8], non-small cell lung [9], glioblastoma [10], and HCC [11].…”

Section: Introductionmentioning

confidence: 99%

TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice

Jiang

Minter

Stratton

et al. 2015

Journal of Hepatology

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Background and Aims Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumor suppressor. To address this dichotomy and uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expresses normal levels of Trim24 lacking only exon 4. Methods To produce germline-deleted Trim24dlE1 mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24LoxP mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24hep) was achieved by crossing with an Albumin-Cre line. Phenotypic analyses were complemented by protein, gene-specific and global RNA expression analyses and quantitative chromatin immunoprecipitation. Results Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid and lipid metabolism genes, as well as increased expression of genes in unfolded protein, endoplasmic reticulum stress and cell cycle pathways. Trim24dlE1/dlE1 mice have markedly depleted visceral fat and, like Trim24hep/hep mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma. Conclusions TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human nonalcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.

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“…Tripartite motif-containing 24 (TRIM24) and microRNA 21 (mir-21) were identified as upstream regulators but were assigned negative activation Z-scores. These two molecules have a negative regulatory role in type I IFN responses (Chen et al, 2013, Tisserand et al, 2011, and their predicted negative activations are again consistent with the observed up-regulation of IFN-α/β responses.…”

Section: Ingenuity's Canonical Pathway Analysis Of Down-regulated Genessupporting

confidence: 69%

“…In some cases, the fever might resolve in one or two days, but return with the so-called 'saddle-back fever' (Hawman et al, 2013, Carey, 1971. After the onset of fever, nearly all patients develop debilitating polyarthritis , White et al, 2001) usually involving peripheral joints (interphalangeal joints, wrists and ankles), proximal joints (knees and elbows) and large joints (shoulders and spine) (Tisserand et al, 2011. Some patients also experience a maculopapular rash (Peck et al, 1979, Ryman et al, 2000 and oedema (Brighton et al, 1983).…”

Section: Acute Symptomsmentioning

confidence: 99%

Understanding immunobiology of chikungunya virus disease using mouse models

Poo¹

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Chikungunya virus (CHIKV) is a mosquito borne alphavirus, whose primary disease manifestation in humans is acute and chronic, often debilitating polyarthritis/polyathralgia. Current treatments are often inadequate. This thesis aims to elucidate the roles of several immune components in CHIKV disease, using a mouse model of CHIKV infection and disease, which recapitulates many aspects of human disease. An improved understanding of the immunobiology of CHIKV is required for future development of new interventions for this recently re-emergent virus.CHIKV polyarthritis/polyathralgia is associated with a prolific monocytes/macrophage infiltration of musculoskeletal tissue in humans, monkeys and mice. The infection in all species is associated with high levels of chemokine (C-C motif) ligand 2 (CCL2), a chemokine that binds chemokine (C-C motif) receptor 2 (CCR2) and is involved in recruitment of monocytes to the sites of infection. Targeting CCL2 or CCR2 signalling has thus been proposed as a potential treatment option for CHIKV disease. Results herein show that CHIKV infection of mice deficient in CCR2 led to a significantly more pronounced and prolonged arthritis that was associated with cartilage (iii) many of the inflammatory pathways identified in chronically infected mouse feet were also found in chronic CHIKV patients. These observations suggest that chronic disease is due to ongoing inflammation stimulated by persistently replicating viral RNA and viral proteins encoded by that RNA (Chapter 5).In conclusion, this thesis has shown, that inflammatory CCR2+ monocyte can be critical for preventing excessive pathology and resolving inflammation, that distinct immune factors control CHIKV viraemia and arthritis, and that long-term persistence of replicating CHIKV RNA might be the cause of protracted arthritic manifestations in CHIKV patients. These studies will hopefully inform future development of intervention for CHIKV.III

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Tripartite Motif 24 (Trim24/Tif1α) Tumor Suppressor Protein Is a Novel Negative Regulator of Interferon (IFN)/Signal Transducers and Activators of Transcription (STAT) Signaling Pathway Acting through Retinoic Acid Receptor α (Rarα) Inhibition

Cited by 67 publications

References 55 publications

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice

Understanding immunobiology of chikungunya virus disease using mouse models

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