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Dual-Specificity Phosphatases in Immunity and Infection: An Update

Lang, Roland, Raffi, Faizal·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20112710PMC PMC6600418
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Abstract

Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins. Finally, the pharmacological targeting of DUSPs is desirable to modulate immune and inflammatory responses.

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Figure 1 Dual-specificity phosphatases (DUSP): domain structure, mode of action, and levels of regulation. The 10 members of the classical DUSP-MAPK phosphatases contain a MAPK-binding kinase-interaction motif (KIM) conferring selective binding to ERK1/2, p38 or JNK1/2. Upon binding to MAPK, the DUSP catalytic domain (DCD) dephosphorylates the TXY motif in the activation loop (right panel). Atypical DUSPs lack a KIM and can have more diverse substrates, including phosphorylated RNA (DUSP11). Regulated expression between cell types and after stimulation, different compartmentalization of DUSP, and selectivity in binding to MAPK family members confers specificity of DUSP action in signaling.
Figure 1 Dual-specificity phosphatases (DUSP): domain structure, mode of action, and levels of regulation. The 10 members of the classical DUSP-MAPK phosphatases contain a MAPK-binding kinase-interaction motif (KIM) conferring selective binding to ERK1/2, p38 or JNK1/2. Upon binding to MAPK, the DUSP catalytic domain (DCD) dephosphorylates the TXY motif in the activation loop (right panel). Atypical DUSPs lack a KIM and can have more diverse substrates, including phosphorylated RNA (DUSP11). Regulated expression between cell types and after stimulation, different compartmentalization of DUSP, and selectivity in binding to MAPK family members confers specificity of DUSP action in signaling.CC BY · PubMed Central
Figure 2 DUSP as regulators and specifiers of innate immune responses. (A) Negative feedback regulation of MAPK signaling by activation-induced DUSP upregulation, shown here as example TLR-induced DUSP1 that is enhanced by IL-10-STAT3 signaling. (B) Ligands for different pattern recognition receptors trigger overlapping yet distinct gene expression programs, including the differential expression of DUSP family members that then tune the amplitude and kinetics of MAPK activation. (C) Activation of the same pattern recognition receptor (here TLR9) in different cell types induces strikingly different cytokine outputs. Differential expression of DUSP genes (here DUSP9 in pDC, but not cDC) contributes to cell type-specificity of signaling and transcriptional responses.
Figure 2 DUSP as regulators and specifiers of innate immune responses. (A) Negative feedback regulation of MAPK signaling by activation-induced DUSP upregulation, shown here as example TLR-induced DUSP1 that is enhanced by IL-10-STAT3 signaling. (B) Ligands for different pattern recognition receptors trigger overlapping yet distinct gene expression programs, including the differential expression of DUSP family members that then tune the amplitude and kinetics of MAPK activation. (C) Activation of the same pattern recognition receptor (here TLR9) in different cell types induces strikingly different cytokine outputs. Differential expression of DUSP genes (here DUSP9 in pDC, but not cDC) contributes to cell type-specificity of signaling and transcriptional responses.CC BY · PubMed Central
Figure 3 Mechanism of DUSP1 regulation of cytokine expression in Toll-like receptor (TLR)-stimulated macrophages. DUSP1 expression is induced after TLR triggering via MAPK activation and strongly enhanced by IL-10-STAT3 signaling. Preferential inhibition of p38 activity by DUSP1 down-regulates the expression of a subset of cytokines by interfering with MSK1/2-dependent transcription factors and through the control of mRNA decay via the post-translational regulation of TTP. See text for references and details.
Figure 3 Mechanism of DUSP1 regulation of cytokine expression in Toll-like receptor (TLR)-stimulated macrophages. DUSP1 expression is induced after TLR triggering via MAPK activation and strongly enhanced by IL-10-STAT3 signaling. Preferential inhibition of p38 activity by DUSP1 down-regulates the expression of a subset of cytokines by interfering with MSK1/2-dependent transcription factors and through the control of mRNA decay via the post-translational regulation of TTP. See text for references and details.CC BY · PubMed Central
Figure 4 Role of DUSP16 in innate and adaptive immune cells. Analysis of CD4+ T cell compartment and myeloid cells derived from radiation chimeras with a DUSP16-deficient hematopoietic system was performed by two labs [104,107].
Figure 4 Role of DUSP16 in innate and adaptive immune cells. Analysis of CD4+ T cell compartment and myeloid cells derived from radiation chimeras with a DUSP16-deficient hematopoietic system was performed by two labs [104,107].CC BY · PubMed Central

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Cited by

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Metadata

Authors
Lang, R., & Raffi, F.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-06-02
Volume
20
Issue
11
Pages
2710
ISSN
1422-0067
DOI
10.3390/ijms20112710
PMC
PMC6600418
Cited by
160
References
8
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Deutsche Forschungsgemeinschaft (SFB 643, A10)
  • IZKF Medical Faculty FAU Erlangen-Nürnberg (F1-11)

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Lang, R., & Raffi, F. (2019). Dual-Specificity Phosphatases in Immunity and Infection: An Update. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20112710