FIC domain-containing protein (FICD) (FICD)

FIC domain-containing protein (FICD), also known as HYPE, is a bifunctional enzyme localized in the endoplasmic reticulum (ER) that serves as a critical regulator of protein homeostasis. It catalyzes both the addition (AMPylation) and removal (de-AMPylation) of an adenosine monophosphate (AMP) moiety from the ER-resident chaperone BiP (HSPA5), thereby acting as a molecular rheostat for the unfolded protein response (UPR). Under low-stress conditions, FICD AMPylates BiP to maintain a reserve of inactive chaperones, while ER stress triggers FICD to de-AMPylate BiP, acutely increasing the pool of active chaperones to assist in protein folding. Dysregulation of FICD activity is linked to various pathologies, including neurodegenerative disorders like hereditary spastic paraplegia and metabolic conditions such as neonatal diabetes. Recent drug discovery efforts have identified small-molecule inhibitors, such as C22 and C73, which target FICD to modulate UPR signaling and improve protein folding in disease contexts.

Other names

HYPEHuntingtin yeast-interacting protein EHIP13HIP-13Protein adenylyltransferase FICDAMPylaseDe-AMPylase FICDAdenosine monophosphate-protein transferase FICD

Inhibition of FICD-mediated AMPylation or de-AMPylation of the ER chaperone BiP (HSPA5) to modulate unfolded protein response (UPR) signaling and restore proteostasis.