In Science Signaling this week, researchers in the US and Europe report that coupled activation and degradation of the eEF2K kinase regulates protein synthesis in response to genotoxic stress. When exposed to stress, the researchers found that eEF2K was activated by AMPK-mediated phosphorylation. The activated eEF2K then phosphorylated eEF2. "Subsequently, during DNA damage checkpoint silencing, a process required to allow cell cycle reentry, eEF2K was degraded by the ubiquitin-proteasome system through the ubiquitin ligase SCFβTrCP (Skp1-Cul1-F-box protein, β-transducin repeat-containing protein) to enable rapid resumption of translation elongation," the authors write. This suggests a link between DNA damage signaling and translation elongation, they add.
Also in Science Signaling this week, a team led by researchers at Johns Hopkins University reports that matrix rigidity controls the endothelial differentiation and morphogenesis of cardiac precursors. The team shows that multipotent cells derived from native cardiac tissue monitor the rigidity of the cell substratum, and that enhanced proliferation, endothelial differentiation, and morphogenesis occur when the rigidity of the cell substratum matches that of the myocardium. "Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms," the authors write. "Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation."
In Science Translational Medicine this week, researchers in France and Switzerland write that pre-existing bacillus Calmette-Guérin-specific T-cells can improve the chances of success of intravesical immunotherapy for bladder cancer. Using an experimental model, the team shows that BCG can disseminate to bladder draining lymph nodes and prime interferon-γ–producing T-cells after a single instillation, but that repeated instillations with live BCG are necessary for a meaningful T-cell infiltration into the bladder. "Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol," the authors write. "Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy."
Also in Science Translational Medicine this week, researchers in the US and Sweden identify naturally occurring fatty acids in the myelin sheath that resolve neuroinflammation. The team used lipid antigen microarrays and lipid mass spectrometry to identify lipid targets of the autoimmune response in the brains of patients with multiple sclerosis, and in an animal model of MS. They found that MS autoantibodies target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. "Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids' saturated fatty acid side chains," the authors write. "Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as therapeutics for MS."