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.
Highlights
Reversible phosphorylation plays a fundamental role in signal transduction in physiological and pathological processes
The inducible expression of DUSP5 in the immune system was first identified in T cells after stimulation with cytokines signaling through the common gamma chain as negative feedback regulator of extracellular signal-regulated kinases (ERK) activation [67]
The conditional deletion of DUSP9 in CD11c-expressing DC did not restore ERK1/2 activation in plasmacytoid DC (pDC) and only weakly reduced IFNβ and IL-12 expression in response to TLR9 stimulation [13]. These results indicate that either the lack of ERK activation in pDC is caused by intrinsic differences in signaling between pDC and conventional DC (cDC), or, alternatively, other phosphatases compensate for the absence of DUSP9, which may include DUSP5, DUSP6 or other dual-specificity phosphatase (DUSP) family members expressed in pDC
Summary
Reversible phosphorylation plays a fundamental role in signal transduction in physiological and pathological processes. Kinases phosphorylate multiple substrates, including other kinases and transcription factors, allowing the rapid transmission of signaling information to the nucleus and cellular responses at the level of gene expression and post-transcriptional regulation The kinases and their substrates required for key biological processes, such as cell proliferation, cytokine or antigen receptor signaling, have been intensively studied by biochemical, genetic and pharmacological methods. The function and specificity of the approximately 200 phosphatases encoded in the human and murine genomes are much less well characterized, the dephosphorylation of proteins and other substrates is an vital molecular switch to initiate or terminate signaling. We will conclude by highlighting, in our opinion, the most important questions for ongoing research on the role of DUSPs in the immune system
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