An international collaboration led by Dr Elton Zeqiraj (University of Leeds, UK) and Prof Roger Greenberg (University of Pennsylvania, US) reported in Nature the cryo-electron microscopy structure of the human BRISC–SHMT2 complex, which is involved in cell metabolism and immune response. The structure showed that (inactive dimeric) SHMT2 inhibits the BRCC36 deubiquitylase activity of BRISC by steric hindrance of the BRCC36 active site. Since pyridoxal-5′-phosphate (PLP, the active form of vitamin B6) stabilizes SHMT2 in an active tetrameric state, the study identified an important mechanism in which a metabolite (PLP) regulates immune signalling by interfering with ubiquitin signalling (i.e. BRISC activity). This insight is important for potential treatments of metabolic and auto-immune diseases.
Walden, M., Tian, L., Ross, R. et al. Metabolic control of BRISC–SHMT2 assembly regulates immune signalling. Nature 570, 194–199 (2019). https://doi.org/10.1038/s41586-019-1232-1