Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling

The NF-κB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-κB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-α- and LPS-mediated NF-κB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-κB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-κB and JNK activation in response to TNF-α, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-α-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-κB activation. Thus, TAX1BP1 is pivotal for the termination of NF-κB and JNK signaling by functioning as an essential regulator of A20

Early intervention in psychosis

In the past 20 years, the evidence confirming the superiority of specialised early intervention services over generic care in managing the critical early phase of psychosis has grown steadily, and specialised early intervention services have been established in many parts of the developed world. The multidisciplinary, comprehensive and assertive approach of early intervention services was based on ground-breaking research showing the importance of minimising the duration of untreated psychosis, defining “at-risk” populations and optimising delivery of evidence-based treatment (psychotropic medication, other medication and non-pharmacological). Whilst studies have repeatedly shown positive short- and medium-term outcomes for early-intervention services, these appear to dissipate once care reverts to generic services. Early intervention in psychosis is now considered one of the most important mental health reforms since the era of deinstitutionalisation. Research efforts are now concentrating on understanding the pathophysiological processes that accompany the emergence and progression of psychosis, improving identification and treatment of at-risk mental states, developing focused early detection strategies and extending the early intervention paradigm to all youth mental health disorders