Dual-specificity MAP kinase (MAPK) phosphatases (DUSPs) are well-established negative modulators in regulating MAPK signaling in mammalian cells and tissues. Our previous studies have shown the ...involvement of DUSP6 in regulating innate immunity in Japanese flounder Paralichthys olivaceus. In order to gain a better understanding of the role of DUSPs in fish innate immunity, in the present study we identified and characterized three additional DUSP genes including DUSP1, 2 and 5 in P. olivaceus. The three Japanese flounder DUSP proteins share common domain structures composed of a conserved N-terminal Rhodanase/CDC25 domain and a C-terminal catalytic phosphatase domain, while they show only less than 26% sequence identities, indicating that they may have different substrate selectivity. In addition, mRNA transcripts of all the three DUSP genes are detected in all examined Japanese flounder tissues; however, DUSP1 is dominantly expressed in spleen while DUSP2 and 5 are primarily expressed in skin. Furthermore, all the three DUSP genes are constitutively expressed in the Japanese flounder head kidney macrophages (HKMs) and peripheral blood leucocytes (PBLs) with unequal distribution patterns. Moreover, all the three DUSPs gene expression was induced differently in response to the LPS and double-stranded RNA mimic poly(I:C) stimulations both in the Japanese flounder HKMs and PBLs, suggesting an association of DUSPs with TLR signaling in fish. Taken together, the co-expression of various DUSPs members together with their different responses to the immune challenges indicate that the DUSP members may operate coordinately in regulating the MAPK-dependent immune responses in the Japanese flounder.
•cDNAs of dual-specificity MAP kinase phosphatases 1, 2 and 5 were identified from Paralichthys olivaceus.•DUSP1, 2 and 5 proteins share common domain structures but show only less than 26% sequence identities.•Dusp1, 2 and 5 are co-expressed in several Japanese flounder tissues and immune cells with unequal distribution patterns.•Dusp1, 2 and 5 were induced by PAMPs challenges in immune cells.
DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one ...substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.
Host specificity of the gut microbiome Mallott, Elizabeth K; Amato, Katherine R
Nature reviews. Microbiology,
10/2021, Volume:
19, Issue:
10
Journal Article
Peer reviewed
Developing general principles of host-microorganism interactions necessitates a robust understanding of the eco-evolutionary processes that structure microbiota. Phylosymbiosis, or patterns of ...microbiome composition that can be predicted by host phylogeny, is a unique framework for interrogating these processes. Identifying the contexts in which phylosymbiosis does and does not occur facilitates an evaluation of the relative importance of different ecological processes in shaping the microbial community. In this Review, we summarize the prevalence of phylosymbiosis across the animal kingdom on the basis of the current literature and explore the microbial community assembly processes and related host traits that contribute to phylosymbiosis. We find that phylosymbiosis is less prevalent in taxonomically richer microbiomes and hypothesize that this pattern is a result of increased stochasticity in the assembly of complex microbial communities. We also note that despite hosting rich microbiomes, mammals commonly exhibit phylosymbiosis. We hypothesize that this pattern is a result of a unique combination of mammalian traits, including viviparous birth, lactation and the co-evolution of haemochorial placentas and the eutherian immune system, which compound to ensure deterministic microbial community assembly. Examining both the individual and the combined importance of these traits in driving phylosymbiosis provides a new framework for research in this area moving forward.
Dual-specificity MAP kinase phosphatases (MKPs) provide a complex negative regulatory network that acts to shape the duration, magnitude and spatiotemporal profile of MAP kinase activities in ...response to both physiological and pathological stimuli. Individual MKPs may exhibit either exquisite specificity towards a single mitogen-activated protein kinase (MAPK) isoform or be able to regulate multiple MAPK pathways in a single cell or tissue. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules. In this review, we explore the current state of knowledge with respect to the regulation of MKP expression levels and activities, the mechanisms by which individual MKPs recognize and interact with different MAPK isoforms and their role in the spatiotemporal regulation of MAPK signalling.
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly
. To define the contribution of immune system ageing to organism ageing, here we ...selectively deleted Ercc1, which encodes a crucial DNA repair protein
, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence
in the immune system only. We show that Vav-iCre
;Ercc1
mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice
. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre
;Ercc1
or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre
;Ercc1
mice with rapamycin reduced markers of senescence in immune cells and improved immune function
. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Dual‐specificity protein phosphatases (DUSPs), which dephosphorylate both phosphoserine/threonine and phosphotyrosine, play vital roles in immune activation, brain function and cell‐growth ...signalling. A family‐wide structural library of human DUSPs was constructed based on experimental structure determination supplemented with homology modelling. The catalytic domain of each individual DUSP has characteristic features in the active site and in surface‐charge distribution, indicating substrate‐interaction specificity. The active‐site loop‐to‐strand switch occurs in a subtype‐specific manner, indicating that the switch process is necessary for characteristic substrate interactions in the corresponding DUSPs. A comprehensive analysis of the activity–inhibition profile and active‐site geometry of DUSPs revealed a novel role of the active‐pocket structure in the substrate specificity of DUSPs. A structure‐based analysis of redox responses indicated that the additional cysteine residues are important for the protection of enzyme activity. The family‐wide structures of DUSPs form a basis for the understanding of phosphorylation‐mediated signal transduction and the development of therapeutics.
Extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated as important regulators of metabolic homeostasis. Here we generated a new mouse model with genetic deletion of two ERK1/2 ...phosphatases, dual specificity phosphatase (DUSP) 6 and 8, to further define the role of ERK1/2 in obesity development. Dusp6/8 double-null mice demonstrated elevated ERK1/2 phosphorylation in multiple tissues, without any change of phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). Elevated ERK1/2 activity in Dusp6/8 double-null mice was associated with larger hearts and other organs, consistent with greater rate of cell proliferation in these mice. However, ERK1/2 activation was not sufficient to protect the mouse hearts from pathological hypertrophy and interstitial fibrosis following angiotensin II and phenylephrine stimulation. Interestingly, mice lacking DUSP6/8 were resistant to high-fat diet-induced obesity. Serum triglyceride, lipid content in the liver and visceral adipose tissues was also dramatically reduced in Dusp6/8 double-null mice. Furthermore, Dusp6/8 double-null mice had improved glucose tolerance. Mechanistically, we found out that elevated ERK1/2 activity increased the expression levels of genes involved in lipid metabolism and glucose homeostasis. Together, our data suggest that ERK1/2 play an essential role for the management of metabolic homeostasis.
Summary
Feedback between plants and soil microbial communities can be a powerful driver of vegetation dynamics. Plants elicit changes in the soil microbiome that either promote or suppress ...conspecifics at the same location, thereby regulating population density‐dependence and species co‐existence. Such effects are often attributed to the accumulation of host‐specific antagonistic or beneficial microbiota in the rhizosphere. However, the identity and host‐specificity of the microbial taxa involved are rarely empirically assessed. Here we review the evidence for host‐specificity in plant‐associated microbes and propose that specific plant–soil feedbacks can also be driven by generalists. We outline the potential mechanisms by which generalist microbial pathogens, mutualists and decomposers can generate differential effects on plant hosts and synthesize existing evidence to predict these effects as a function of plant investments into defence, microbial mutualists and dispersal. Importantly, the capacity of generalist microbiota to drive plant–soil feedbacks depends not only on the traits of individual plants but also on the phylogenetic and functional diversity of plant communities. Identifying factors that promote specialization or generalism in plant–microbial interactions and thereby modulate the impact of microbiota on plant performance will advance our understanding of the mechanisms underlying plant–soil feedback and the ways it contributes to plant co‐existence.
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