The success of high throughput sequencing programmes, including the Human Genome Project led to the 'identification' of a large number of novel genes of completely unknown function. Since then, many ...of these genes have been subject to functional studies focussed on uncovering their biological importance. Recent advances in genome-wide screening of DNA sequence variants as well as focussed genetic studies identified a number of candidate loci contributing to the development of complex diseases, including those affecting lipid homeostasis. An excellent example for the convergence of genetics and experimental biology is the tribbles gene family which was among those identified both in recent genetic studies and were implicated in dysregulation of lipid levels experimentally. Thus, there is a need now to take a step back and reconcile these findings accumulated over recent years.
Allelic variants of tribbles proteins have been associated with the control of fatty acid synthesis and insulin resistance as well as regulating plasma triglyceride and HDL cholesterol levels. Several mechanisms of molecular action have been proposed for the tribbles mediated control of these processes, including the regulation of signalling events, protein turnover and transcription, sometimes with conflicting evidence emerging.
This review attempts to synthesize knowledge obtained on the biology of the tribbles protein family in the context of lipid metabolism as well as discussing the recently emerging genetic evidence for the importance of these proteins in human disease.
Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or ...sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) ...has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novelmechanism for therapeutic interventions in STING-associated inflammatory diseases.
Abstract Background Streptococcus pyogenes–related skin infections are increasingly implicated in the development of rheumatic heart disease (RHD) in lower-resource settings, where they are often ...associated with scabies. The true prevalence of S pyogenes–related pyoderma may be underestimated by bacterial culture. Methods A multiplex quantitative polymerase chain reaction (qPCR) assay for S pyogenes, Staphylococcus aureus, and Sarcoptes scabiei was applied to 250 pyoderma swabs from a cross-sectional study of children aged <5 years in The Gambia. Direct PCR-based emm-typing was used to supplement previous whole genome sequencing (WGS) of cultured isolates. Results Pyoderma lesions with S pyogenes increased from 51% (127/250) using culture to 80% (199/250) with qPCR. Compared to qPCR, the sensitivity of culture was 95.4% for S pyogenes (95% confidence interval {CI}, 77.2%–99.9%) in samples with S pyogenes alone (22/250 9%), but 59.9% (95% CI, 52.3%–67.2%) for samples with S aureus coinfection (177/250 71%). Direct PCR-based emm-typing was successful in 50% (46/92) of cases, identifying 27 emm-types, including 6 not identified by WGS (total 52 emm-types). Conclusions Bacterial culture significantly underestimates the burden of S pyogenes in pyoderma, particularly with S aureus coinfection. Molecular methods should be used to enhance the detection of S pyogenes in surveillance studies and clinical trials of preventive measures in RHD-endemic settings.
Hospital outbreaks of COVID19 result in considerable mortality and disruption to healthcare services and yet little is known about transmission within this setting. We characterise within hospital ...transmission by combining viral genomic and epidemiological data using Bayesian modelling amongst 2181 patients and healthcare workers from a large UK NHS Trust. Transmission events were compared between Wave 1 (1st March to 25th J'uly 2020) and Wave 2 (30th November 2020 to 24th January 2021). We show that staff-to-staff transmissions reduced from 31.6% to 12.9% of all infections. Patient-to-patient transmissions increased from 27.1% to 52.1%. 40%-50% of hospital-onset patient cases resulted in onward transmission compared to 4% of community-acquired cases. Control measures introduced during the pandemic likely reduced transmissions between healthcare workers but were insufficient to prevent increasing numbers of patient-to-patient transmissions. As hospital-acquired cases drive most onward transmission, earlier identification of nosocomial cases will be required to break hospital transmission chains.
Development of the atherosclerotic plaque involves a complex interplay between a number of cell types and an extensive inter-cellular communication via cell bound as well as soluble mediators. The ...family of tribbles proteins has recently been identified as novel controllers of pro-inflammatory signal transduction. The objective of this study was to address the expression pattern of all three tribbles proteins in atherosclerotic plaques from a mouse model of atherosclerosis. Each tribbles were expressed in vascular smooth muscle cells, endothelial cells as well as in resident macrophages of mouse atherosclerotic plaques. The role of IL-1 mediated inflammatory events in controlling tribbles expression was also addressed by inducing experimental atherosclerosis in ApoE-/-IL1R1-/- (double knockout) mice. Immunohistochemical analysis of these mice showed a selective decrease in the percentage of trb-1 expressing macrophages, compared to the ApoE-/- cohort (14.7% ± 1.55 vs. 26.3% ± 1.19). The biological significance of this finding was verified in vitro where overexpression of trb-1 in macrophages led to a significant attenuation (~70%) of IL-6 production as well as a suppressed IL-12 expression induced by a proinflammatory stimulus. In this in vitro setting, expression of truncated trb-1 mutants suggests that the kinase domain of this protein is sufficient to exert this inhibitory action.
The importance of the
BCR
and
TLR
9 in autoimmunity and in the production of auto‐antibodies is well established but the underlying molecular mechanism still needs to be determined. Here, we aim to ...characterize the
BCR
‐
TLR
9 cross‐talk by its effect on
T
‐bet, as
T
‐bet is activated and regulated by both receptors and has an important role in class‐switching to pathological
I
g
G
2a in mice. Using primary mouse
B
cells, we demonstrate that
T
‐bet expression is synergistically elevated by the cross‐talk between the
BCR
and
TLR
9. To test the effect of this synergy on
I
g
G
2a‐switching, the levels of switched
B
cells were checked by functional tests. We found that
BCR
costimulation had no additional effect on
TLR
9‐induced
I
g
G
2a expression, however the expression of
R
ad51 was synergistically increased. To check the biological significance of the synergy, we compared
T
‐bet expression in
B
cells from healthy and collagen‐induced arthritis mice but no differences were found. Taken together, we demonstrate here that signaling cascades driven by the
BCR
and
TLR
9 have a newly identified meeting point at
T
‐bet. The two cascades act synergistically on
T
‐bet; however additional signals may be needed to induce prolonged functional responses such as class‐switch recombination.
Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has ...emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.
The importance of the BCR and TLR9 in autoimmunity and in the production of auto‐antibodies is well established but the underlying molecular mechanism still needs to be determined. Here, we aim to ...characterize the BCR‐TLR9 cross‐talk by its effect on T‐bet, as T‐bet is activated and regulated by both receptors and has an important role in class‐switching to pathological IgG2a in mice. Using primary mouse B cells, we demonstrate that T‐bet expression is synergistically elevated by the cross‐talk between the BCR and TLR9. To test the effect of this synergy on IgG2a‐switching, the levels of switched B cells were checked by functional tests. We found that BCR costimulation had no additional effect on TLR9‐induced IgG2a expression, however the expression of Rad51 was synergistically increased. To check the biological significance of the synergy, we compared T‐bet expression in B cells from healthy and collagen‐induced arthritis mice but no differences were found. Taken together, we demonstrate here that signaling cascades driven by the BCR and TLR9 have a newly identified meeting point at T‐bet. The two cascades act synergistically on T‐bet; however additional signals may be needed to induce prolonged functional responses such as class‐switch recombination.
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