Limits...
FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

Nie J, Li YY, Zheng SG, Tsun A, Li B - Front Immunol (2015)

Bottom Line: Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans.In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals.Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.

ABSTRACT
CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.

No MeSH data available.


Related in: MedlinePlus

The post-translational modification of FOXP3. The post-translational modifications that affect FOXP3 stability and transcriptional activity. FOXP3 protein is ubiquitinated, acetylated and phosphorylated by various post-translational modification enzymes.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585344&req=5

Figure 3: The post-translational modification of FOXP3. The post-translational modifications that affect FOXP3 stability and transcriptional activity. FOXP3 protein is ubiquitinated, acetylated and phosphorylated by various post-translational modification enzymes.

Mentions: The post-translational modifications of FOXP3 affect Treg differentiation, function, and phenotypic commitment through regulating FOXP3 protein stability and transcriptional activity (Figure 3). Several previous studies have reported that FOXP3 protein stability is controlled by ubiquitination-mediated degradation. Under inflammatory conditions, STUB1 was found recruited to FOXP3 by HSP70 to polyubiquitinate FOXP3 at its K227/250/263/268 sites in a K48-linked polyubiquitination manner. K48-linked polyubiquitinated FOXP3 is further led to proteasome-mediated degradation. Manipulating the level of STUB1 in Treg cells through ectopic expression or knockdown directly affected the protein levels of FOXP3, signature Treg gene expression and the ability to suppress inflammatory immune responses (111). On the other hand, the deubiquitinase USP7 is able to deubiquitinate FOXP3 in an HSP90-dependent manner and stabilizes FOXP3 to increase Treg number to enhance Treg suppressive activity (112). HIF1a and PKB/Akt1-mediated FOXP3 phosphorylation also affects FOXP3 stabilization through indirectly regulating FOXP3 ubiquitination levels (113–116).


FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

Nie J, Li YY, Zheng SG, Tsun A, Li B - Front Immunol (2015)

The post-translational modification of FOXP3. The post-translational modifications that affect FOXP3 stability and transcriptional activity. FOXP3 protein is ubiquitinated, acetylated and phosphorylated by various post-translational modification enzymes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585344&req=5

Figure 3: The post-translational modification of FOXP3. The post-translational modifications that affect FOXP3 stability and transcriptional activity. FOXP3 protein is ubiquitinated, acetylated and phosphorylated by various post-translational modification enzymes.
Mentions: The post-translational modifications of FOXP3 affect Treg differentiation, function, and phenotypic commitment through regulating FOXP3 protein stability and transcriptional activity (Figure 3). Several previous studies have reported that FOXP3 protein stability is controlled by ubiquitination-mediated degradation. Under inflammatory conditions, STUB1 was found recruited to FOXP3 by HSP70 to polyubiquitinate FOXP3 at its K227/250/263/268 sites in a K48-linked polyubiquitination manner. K48-linked polyubiquitinated FOXP3 is further led to proteasome-mediated degradation. Manipulating the level of STUB1 in Treg cells through ectopic expression or knockdown directly affected the protein levels of FOXP3, signature Treg gene expression and the ability to suppress inflammatory immune responses (111). On the other hand, the deubiquitinase USP7 is able to deubiquitinate FOXP3 in an HSP90-dependent manner and stabilizes FOXP3 to increase Treg number to enhance Treg suppressive activity (112). HIF1a and PKB/Akt1-mediated FOXP3 phosphorylation also affects FOXP3 stabilization through indirectly regulating FOXP3 ubiquitination levels (113–116).

Bottom Line: Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans.In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals.Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.

ABSTRACT
CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.

No MeSH data available.


Related in: MedlinePlus