Nuclear cathepsin B-like protease cleaves transcription factor YY1 in differentiated cells

Pizzorno, Marie C.

doi:10.1016/s0925-4439(01)00032-1

Cited by 19 publications

(15 citation statements)

References 47 publications

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“…Activation of macrophages by LPS induces expression of Q-SNARE components synthaxin 4 and SNAP-23 to accommodate the increased trafficking during TNF-␣ secretion (38). Cathepsins such as cathepsin L (39) or cathepsin B (40,41) can be localized in the nucleus and regulate transcription factors. We did not detect differences in the levels of synthaxin 4 and SNAP-23 in CAMe-treated or Ctsb Ϫ/Ϫ macrophages (data not shown), suggesting that cathepsin B is not inhibiting fusion of TNF-␣-containing vesicles to the plasma membrane by down-regulating these SNARE components.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Martins

Khazaie

et al. 2008

The Journal of Immunology

111

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TNF-α is a potent proinflammatory cytokine, essential for initiating innate immune responses against invading microbes and a key mediator involved in the pathogenesis of acute and chronic inflammatory diseases. To identify molecules involved in the production of TNF-α, we used a functional gene identification method using retroviral integration-mediated mutagenesis, followed by LPS-stimulated TNF-α production analysis in macrophages. We found that cathepsin B, a lysosomal cysteine proteinase, was required for optimal posttranslational processing of TNF-α in response to the bacterial cell wall component LPS. Mouse bone marrow-derived macrophages from cathepsin B-deficient mice and macrophages treated with the cathepsin B-specific chemical inhibitor CA074 methyl ester or small interfering RNA against cathepsin B secreted significantly less TNF-α than wild-type or nontreated macrophages. We further showed that the inhibition of cathepsin B caused accumulation of 26-kDa pro-TNF-containing vesicles. Ectopic expression of GFP-conjugated pro-TNF further suggests that pro-TNF failed to reach the plasma membrane without intracellular cathepsin B activity. Altogether, these data suggest that intracellular cathepsin B activity is involved in the TNF-α-containing vesicle trafficking to the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Martins

Khazaie

et al. 2008

The Journal of Immunology

111

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“…However, during differentiation to myotubes, this repression is lifted due to the proteolytic degradation of YY1 (Lee et al, 1994;Galvagni et al, 1998;Walowitz et al, 1998). It is interesting to note, therefore, that there is at least one report which suggests that the decrease in YY1 protein during the differentiation of T2 cells is due to proteolysis (Pizzorno, 2001). …”

Section: Discussionmentioning

confidence: 99%

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Bain

Mendelson

Sinclair

2003

Journal of General Virology

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The repression of human cytomegalovirus immediate-early (IE) lytic gene expression is crucial for the maintenance of the latent viral state. By using conditionally permissive cell lines, which provide a good model for the differentiation state-dependent repression of IE gene expression, we have identified several cellular factors that bind to the major immediate-early promoter (MIEP) and whose expression is down-regulated after differentiation to a permissive phenotype. Here we show that the cellular protein Ets-2 Repressor Factor (ERF) physically interacts with the MIEP and represses MIEP activity in undifferentiated non-permissive T2 embryonal carcinoma cells. This factor binds to the dyad element and the 21 bp repeats within the MIEP -regions known to be important for the negative regulation of MIEP activity. Finally, we show that following differentiation to a permissive phenotype ERF's repressive effects are severely abrogated. INTRODUCTIONHuman cytomegalovirus (HCMV) is a betaherpesvirus whose sero-prevalence can vary from 50 to 90 % depending on the socio-economic status of the population. Following primary infection, which rarely causes disease in the immunocompetent, HCMV maintains a latent infection throughout the lifetime of the infected host. However, infection or reactivation in the immunocompromised, such as transplant recipients or AIDS patients, is associated with morbidity and mortality (reviewed in Alford & Britt, 1993).Productive HCMV infection and reactivation require an ordered cascade of gene expression and are dependent on the expression of the immediate-early (IE) gene products IE72 and IE86 (also known as IE1 and IE2 respectively). These IE proteins are potent and promiscuous transactivators of both cellular and viral genes, and serve to activate the viral early (E) gene promoters (Pizzorno et al., 1988;Malone et al., 1990), ultimately leading to viral DNA replication, expression of the viral late (L) genes and virus assembly. The expression of IE72 and IE86 is under the control of the major immediate-early promoter (MIEP), a highly complex region comprising a TATA box, an upstream imperfect dyad symmetry element (also termed the modulator), and an extremely powerful enhancer region made up of a series of 17, 18, 19 and 21 bp repeat motifs (reviewed in Meier & Stinski, 1996). MIEP activity is regulated by a myriad of positively and negatively acting cellular and viral proteins. For example, there are numerous nuclear factor-1 (NF-1) sites within the MIEP and the 18 and 19 bp repeat sequences contain NF-kB and cyclic AMPresponsive element binding protein (CREB) binding sites respectively (Meier & Stinski, 1996). Conversely, several studies using non-permissive cells have shown that the modulator and the 21 bp repeats are responsible for the inhibition of MIEP activity in such cells (Nelson et al., 1987;Lubon et al., 1989;Kothari et al., 1991).In vivo, monocytes have been identified as an important site of HCMV latency (Taylor-Wiedeman et al., 1991); these cells carry the viral genome in t...

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“…Specifically, YY1 was shown to be the target of calpein II in a mechanism aimed at downregulating YY1 protein during muscle development (Walowitz et al 1998), which generates a 40 kDa polypeptide. Moreover, a nuclear cathepsin B-like protease activity appears to degrade YY1 (Pizzorno 2001) generating two fragments of about 30 and 40 kDa, a phenomenon associated with the progression of undifferentiated to differentiated NT2 cells upon treatment with retinoic acid. In this case, the larger cleavage product, representing the carboxy-terminal portion of YY1 containing the zinc-finger domain, was shown to bind the cognate DNA consensus forming a faster complex in gel shift assays.…”

Section: Discussionmentioning

confidence: 99%

YY1 binding within the human HSD3B2 gene intron 1 is required for maximal basal promoter activity: identification of YY1 as the 3beta1-A factor

Foti¹,

Reichardt²

2004

Journal of Molecular Endocrinology

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The oxidation and isomerization of 3 -hydroxy-5-ene steroids into keto-4-ene steroids, a pivotal step in the synthesis of all hormonal steroids, is catalyzed by several isoforms of 3 -hydroxysteroid dehydrogenase. In humans, two highly homologous isoforms exist, type I expressed by the HSD3B1 gene in peripheral tissues, and type II expressed by the HSD3B2 gene in steroidogenic organs. Previously, it was shown that the HSD3B1 gene 3 1-A element, encompassing 24 nucleotides of intron 1 not perfectly conserved between the two genes and overlapping with a conserved TG box, contributes to maximal basal promoter activity by binding the ubiquitous and unidentified 3 1-A transcription factor. In this study for the first time we report that similarly, the HSD3B2 gene intron 1 is required for maximal basal promoter activity in reporter gene analyses, as lack of intron 1 results in a 4-to 10-fold reduction in promoter activity. Mutational analysis in gel shift assays revealed that the 3 1-A factor binds both the HSD3B2 and HSD3B1 gene intron 1 by requiring only seven nucleotides of a conserved segment within the 3 1-A element. By competition analysis and use of anti-YY1 antibody in both gel shift and Western blot experiments, we identified the 3 1-A protein as the ubiquitous transcription factor YY1. In addition, we have characterized another similar YY1 binding site differently located with respect to the 3 1-A element in both genes. Deletion and mutational analysis in transient transfections experiments revealed that contrarily to as previously shown for the HSD3B1 gene, lack of YY1 binding to the type II 3 1-A element only results in a marginal reduction of basal promoter activity. Instead, YY1 binding to the second site, placed 35 bp downstream from the 3 1-A element, strongly activates the HSD3B2 gene basal promoter activity, as preventing YY1 binding to this region caused a 50% decrease of basal transcription. Complete abrogation of YY1 binding within type II intron 1 resulted in a gene reporter activity identical to a reporter construct lacking the whole intron 1. These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. Similarities and dissimilarities between YY1 binding within the HSD3B1 and HSD3B2 gene intron 1 are discussed involving the conserved intron 1 TG box, that suggests different mechanisms are implicated in the YY1-mediated stimulation of these two genes basal promoter activity.

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Nuclear cathepsin B-like protease cleaves transcription factor YY1 in differentiated cells

Cited by 19 publications

References 47 publications

Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

YY1 binding within the human HSD3B2 gene intron 1 is required for maximal basal promoter activity: identification of YY1 as the 3beta1-A factor

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