T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1)

Previous studies suggest that localization of tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family members is important for regulating their signal transduction. During a screen for TRAF3-associated proteins that potentially alter TRAF3 subcellular localization and enable signal transduction, we identified a novel protein, T3JAM (TRAF3-interacting Jun N-terminal kinase (JNK)-activating modulator). This protein associates specifically with TRAF3 but not other TRAF family members. Coexpression of T3JAM with TRAF3 recruits TRAF3 to the detergent-insoluble fraction. More importantly, T3JAM and TRAF3 synergistically activate JNK but not nuclear factor (NF)-kappaB. Our studies indicate that T3JAM may function as an adapter molecule that specifically regulates TRAF3-mediated JNK activation.     

Membrane localization of TRAF 3 enables JNK activation

Members of the tumor necrosis factor receptor family as well as other receptors achieve their diverse biological effects through the activation of intracellular signals including the c-Jun N-terminal kinase (JNK) pathway. Such signals are believed to be delivered through mediators known as TNF receptor-associated factors (TRAFs). Although the N-terminal zinc finger region of TRAFs has been shown to be essential for downstream signaling, there is no indication yet as to the nature of its role or of the factors that distinguish the N terminus of TRAF 3, which does not activate JNK in the systems examined thus far, from those of other TRAFs, which do activate this pathway. In the present study, it is shown that, among the known TRAFs, localization to the insoluble cell pellet fraction consistently correlates with JNK activation and that both characteristics map to the TRAF N terminus. Furthermore, it is demonstrated that forced localization of TRAF 3 to the cell membrane is sufficient to convert this molecule into an activator of JNK. This suggests that one of the roles of the TRAF N terminus may be to participate in interactions that promote the recruitment of TRAFs to the membrane and that this localization effect plays an important role in TRAF-mediated JNK activation.     

Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target

Traumatic brain injury (TBI) is known as an acute degenerative pathology of the central nervous system, and has been shown to increase brain aquaporin 4 (AQP4) expression. Various molecular mechanisms affect AQP4 expression, including neuronal high mobility group box 1, forkhead box O3a, vascular endothelial growth factor, hypoxia-inducible factor-1 α (HIF-1 α) sirtuin 2, NF-κB, Malat1, nerve growth factor and Angiotensin II receptor type 1. In addition, inhibition of AQP4 with FK-506, MK-801 (indirectly by targeting N-methyl-d-aspartate receptor), inactivation of adenosine A2A receptor, levetiracetam, adjudin, progesterone, estrogen, V1aR inhibitor, hypertonic saline, erythropoietin, poloxamer 188, brilliant blue G, HIF-1alpha inhibitor, normobaric oxygen therapy, astaxanthin, epigallocatechin-3-gallate, sesamin, thaliporphine, magnesium, prebiotic fiber, resveratrol and omega-3, as well as AQP4 gene silencing lead to reduced edema upon TBI. This review summarizes current knowledge and evidence on the relationship between AQP4 and TBI, and the potential mechanisms involved.