Biogenesis of <scp>TNF</scp> ‐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.