Biogenesis of TNF ‐α‐insights into proteostasis and inflammation

Tumour necrosis factor‐α (TNF‐α) is a central pro‐inflammatory cytokine whose biogenesis, secretion, and signalling are tightly interconnected with cellular protein‐quality control systems. Current evidence shows that TNF‐α maturation, co‐translational and post‐modifications, ER‐luminal folding and trimerisation, Golgi trafficking, and ectodomain shedding by ADAM17 are constrained by ER chaperones and ER‐associated degradation (ERAD). Furthermore, TNF‐α signalling reciprocally interfaces with the proteostasis network (PN) largely through inflammatory stress pathways such as NF‐κB‐dependent transcriptional control of chaperones, ubiquitin‐proteasome components, and autophagy regulators. However, dysregulation of this bidirectional crosstalk mechanistically contributes to disease, including chronic inflammatory disorders, cancer, and degenerative diseases. In this study we provide a synthesis of the current literature on pathways related to protein homeostasis control that determines whether TNF‐α exposure is adaptive or proteotoxic. We also discuss the translational implications this could have by including rational combinations of TNF‐α targeted blockers with PN modulators (chemical chaperones, proteasome or autophagy modulators), which reduce the proteotoxic burden. Therefore, understanding the crosstalk between TNF‐α signalling and components of the PN system promises new mechanistic insights and translational targets for TNF‐α‐driven diseases.