TNFalphaconverting

TNF-alpha converting enzyme, also known as TNFα-converting enzyme or TACE, is a metalloprotease belonging to the ADAM family. It cleaves the membrane-anchored precursor of tumor necrosis factor-alpha (TNF-α) to release the soluble cytokine TNF-α, a key mediator of inflammation. By acting as a sheddase, it converts the membrane-bound form into its soluble form, enabling systemic signaling.

ADAM17 is widely expressed and its activity is tightly controlled. Its proteolytic action is Zn2+-dependent and occurs at the extracellular juxtamembrane region of substrates. Activation and trafficking to the cell surface are regulated by regulatory proteins including iRhom2, which govern maturation and surface expression in immune cells. Signaling pathways such as MAPK can modulate ADAM17 activity and substrate shedding in response to stimuli like lipopolysaccharide (LPS) or phorbol esters.

Substrates: besides TNF-α, ADAM17 sheds a broad range including TNF receptors, L-selectin, and various epidermal growth factor receptor (EGFR) ligands such as TGF-α, amphiregulin, and HB-EGF. This broad substrate spectrum links ADAM17 to inflammatory responses, tissue remodeling, and development.

Structure: ADAM17 is a type I transmembrane protein with a pro-domain that keeps the enzyme inactive until removal by proprotein convertases; it contains a metalloprotease catalytic domain, a disintegrin domain, a cysteine-rich region, a transmembrane segment, and a short cytoplasmic tail. The enzyme is synthesized as an inactive zymogen and matures via furin-like convertases.

Clinical relevance: Dysregulation of ADAM17 activity has been implicated in inflammatory diseases, autoimmune disorders, and cancer. Therapeutic strategies have pursued selective inhibition to reduce TNF-α shedding; however, broad substrate range poses challenges for safety and efficacy. Experimental inhibitors include TAPI-1 and TAPI-2; more selective approaches focus on regulating trafficking via iRhom2 or targeting specific substrate interactions.

Discovery: The TNF-α converting enzyme was identified in the late 1990s as the protease responsible for TNF-α shedding and was subsequently named TACE; its role as a regulator of multiple signaling pathways broadened its recognition as a central mediator of inflammation and signaling.