## Membrane lymphotoxin-α$$_2$$β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

Please always quote using this URN: urn:nbn:de:bvb:20-opus-260077
• In the early 1990s, it has been described that LTα and LTβ form LTα$$_2$$β and LTαβ$$_2$$ heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ$$_2$$–LTβR system has been intensively studied while the LTα$$_2$$β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα$$_2$$β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα$$_2$$β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrateIn the early 1990s, it has been described that LTα and LTβ form LTα$$_2$$β and LTαβ$$_2$$ heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ$$_2$$–LTβR system has been intensively studied while the LTα$$_2$$β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα$$_2$$β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα$$_2$$β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα$$_2$$β (memLTα$$_2$$β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα$$_2$$β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.