A proteomic perspective on TNF-mediated signalling and cell death

The tumour necrosis factor (TNF) is the most potent inducer of cell death amongst cytokines. It is crucial for processes including homeostasis, the development of the immune system and fighting infections. However, high levels of TNF due to genetic disorders or persistent infections can contribute to autoinflammatory and autoimmune diseases or life-threatening conditions like sepsis. These diseases generally display increased levels of cell death, which, downstream of the TNF receptor, can either be caspase-dependent (apoptosis) or caspase-independent (necroptosis). Significant efforts have been invested in unravelling and manipulating signalling mechanisms regulating these two different types of cell death. Here I discuss how modern proteomic approaches like phosphoproteomics and secretomics provide a novel perspective on this central cytokine and its effect on inflammation and cell survival.