Dual-Specificity Phosphatases in Immunity and Infection: An Update

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.

Dose-dependent phorbol 12-myristate-13-acetate-mediated monocyte-to-macrophage differentiation induces unique proteomic signatures in THP-1 cells

“…Our analysis further highlights differentiation protocol-specific subsets with several protein kinases serving as central hubs in mediating the differentiation process. This is of vital importance as cellular signaling is largely governed by the regulation of expression of kinases and phosphatases in a cell type-specific manner or upon cell activation (51-53). One of the major findings of this study is the differential expression of key regulatory kinases implicated in cell cycle regulation including cyclin-dependent kinases, NEK family of serine-threonine kinases as well as cAMP/PKA-induced signaling that are collectively responsible for enrichment of signaling pathways involved in differentiation, maturation, and regulation of actin cytoskeleton dynamics (54, 55).…”

Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase

“…Beyond the essential role in poxvirus infection, DUSPs are important regulators of many cellular signaling pathways. Many DUSP genes are implicated in human diseases affecting immunity and infection (37), cancer, muscle disorders, neurological (38), cardiovascular, and inflammatory diseases (39). The suit of methods described in our study may be useful for examining protein-protein interactions of these other enzyme-substrate combinations.…”

DUSP11 Attenuates Lipopolysaccharide-Induced Macrophage Activation by Targeting TAK1

“…Furthermore, it is important to characterize the structure-function relationships between DUSP11 and TAK1 in immune cells upon TLR signaling. Besides DUSP11 and DUSP14, several DUSP family members play important roles in immune cell activation, inflammatory responses (6,7,(26)(27)(28)(29)(30)(31)(32), or tumorigenesis (33)(34)(35). These findings suggest that DUSP family members have individual functions, instead of redundant roles, in regulation of various immune cell signaling pathways.…”

“…Classical DUSPs, also named as MAPK phosphatases (MKPs), contain the KIM motif, an N-terminal Cdc25 homology domain, and a highly conserved C-terminal phosphatase domain. The structure of atypical DUSPs are relatively simpler, contrasting to classical DUSPs; they lack the KIM motif and Nterminal Cdc25 homology domain (5)(6)(7). DUSP 11 (DUSP11, also named RIP1) is an atypical DUSP and is known to be an RNA triphosphatase (8,9).…”