Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway

Yamashita, Masakatsu; Shinnakasu, Ryo; Asou, Hikari K.; Kimura, Motoko; Hasegawa, Akira; Hashimoto, Kimio; Hatano, Naoya; Ogata, Masato; Nakayama, Toshinori

doi:10.1074/jbc.m502333200

Cited by 145 publications

(133 citation statements)

References 65 publications

(65 reference statements)

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…The hyperacetylation of histones associated with the Th2 cytokine gene locus is dependent on the expression of GATA3 (43,46). Activation of the ERK-MAPK cascade is required for GATA3-dependent histone H3 hyperacetylation of the Th2 cytokine gene locus (16). Consequently, we wished to examine the chromatin remodeling of the Th2 cytokine gene locus in CD4 ϩ T cells from aging mice.…”

Section: Chromatin Remodeling Of the Th2 Cytokine Gene Locus In Cd4 ϩmentioning

confidence: 99%

“…The methods for the generation of the virus supernatant and infection were described previously (16).…”

Section: Retroviral Vectors and Infectionmentioning

confidence: 99%

“…cDNA for human GATA3 was inserted into a multicloning site of pMX-IRES-GFP (16). The methods for the generation of the virus supernatant and infection were described previously (16).…”

Section: Retroviral Vectors and Infectionmentioning

confidence: 99%

“…Among them, GATA3 appears to be a master transcription factor for Th2 cell differentiation (10 -13) and Th2 cell maintenance (14,15). Recently, we reported that the activation of the ERK MAPK cascade inhibits the ubiquitin-dependent degradation of GATA3 in developing Th2 cells and facilitates GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus (16).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Hasegawa

Miki

Hosokawa

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Age-related changes in lymphocytes are most prominent in the T cell compartment. There have been substantial numbers of reports on T cell function in aged mice and humans, such as on the production of Th1 and Th2 cytokines, but the results show considerable variation and contradictions. In the present study, we used 8- to 12-mo-old aging mice and a well-established in vitro Th1/Th2 cell differentiation culture system to identify molecular defects in Th1/Th2 cell differentiation that can be detected in the relatively early stages of aging. The capability to differentiate into Th2 cells is reduced in aging mouse CD4+ T cells. Decreased activation of the ERK MAPK cascade upon TCR stimulation, but normal intracellular-free calcium ion concentration mobilization and normal IL-4-induced STAT6 activation were observed in aging mouse CD4+ T cells. In addition, reduced expression of GATA3 was detected in developing Th2 cells. Chromatin remodeling of the Th2 cytokine gene locus was found to be impaired. Th2-dependent allergic airway inflammation was milder in aging mice compared with in young adult mice. These results suggest that the levels of Th2 cell differentiation and resulting Th2-dependent immune responses, including allergic airway inflammation, decline during aging through defects in the activation of the ERK MAPK cascade, expression of GATA3 protein and GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus. In the present study, we provide the first evidence indicating that a chromatin-remodeling event in T cells is impaired by aging.

show abstract

Section: Chromatin Remodeling Of the Th2 Cytokine Gene Locus In Cd4 ϩmentioning

confidence: 99%

“…The methods for the generation of the virus supernatant and infection were described previously (16).…”

Section: Retroviral Vectors and Infectionmentioning

confidence: 99%

“…cDNA for human GATA3 was inserted into a multicloning site of pMX-IRES-GFP (16). The methods for the generation of the virus supernatant and infection were described previously (16).…”

Section: Retroviral Vectors and Infectionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Hasegawa

Miki

Hosokawa

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to the transcriptional regulation, the expression of GATA3 is also regulated by a posttranscriptional mechanism. We recently reported that the Ras-ERK MAPK cascade controls GATA3 stability through the ubiquitin/ proteasome-dependent pathway (21).…”

mentioning

confidence: 99%

Critical YxKxHxxxRP Motif in the C-Terminal Region of GATA3 for Its DNA Binding and Function

Shinnakasu

Yamashita

Shinoda

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

A zinc finger transcription factor, GATA3, plays an essential role in the development of T cells and the functional differentiation into type 2 Th cells. Two transactivation domains and two zinc finger regions are known to be important for the GATA3 function, whereas the role for other regions remains unclear. In this study we demonstrated that a conserved YxKxHxxxRP motif (aa 345–354) adjacent to the C-terminal zinc finger domain of GATA3 plays a critical in its DNA binding and functions, including transcriptional activity, the ability to induce chromatin remodeling of the Th2 cytokine gene loci, and Th2 cell differentiation. A single point mutation of the key amino acid (Y, K, H, R, and P) in the motif abrogated GATA3 functions. A computer simulation analysis based on the solution structure of the chicken GATA1/DNA complex supported the importance of this motif in GATA3 DNA binding. Thus, we identified a novel conserved YxKxHxxxRP motif adjacent to the C-terminal zinc finger domain of GATA3 that is indispensable for GATA3 DNA binding and functions.

show abstract

USP4 interacts and positively regulates IRF8 function via K48‐linked deubiquitination in regulatory T cells

et al. 2017

View full text Add to dashboard Cite

CD4 CD25 regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells.

show abstract

Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway

Cited by 145 publications

References 65 publications

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Critical YxKxHxxxRP Motif in the C-Terminal Region of GATA3 for Its DNA Binding and Function

USP4 interacts and positively regulates IRF8 function via K48‐linked deubiquitination in regulatory T cells

Contact Info

Product

Resources

About