The programmed necrosis induced by TNF-α requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. One component of these complexes is the mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form). Knockdown of either form attenuated necrosis induced by TNF-α as well as reactive oxygen species (ROS) and calcium ionophore, whereas knockdown of RIP3 and MLKL blocked only TNF-α-mediated necrosis. Upon necrosis induction, PGAM5S recruited the mitochondrial fission factor Drp1 and activated its GTPase activity by dephosphorylating the serine 637 site of Drp1. Drp1 activation caused mitochondrial fragmentation, an early and obligatory step for necrosis execution. These data defined PGAM5 as the convergent point for multiple necrosis pathways.
Tobias has extensive work experience in an international environment covering 4 different countries across 4 continents (Singapore, Germany, USA and China) with profound domain knowledge in the automotive industry. Early in his career Tobias was shaping automotive R&D development projects at Bosch for global OEM customers. His further steps included global Project Management, Management Consulting and via a Management Trainee program he progressed into Regional Product Management. As an Innovation Evangelist Tobias always looks for new technology solutions paired with creative business models to drive business and shape a better future.