Mesencephalic astrocyte-derived neurotrophic factor (MANF) interacting proteins (MANF interactome)

The MANF-related molecular partners comprise a conserved network of proteins that interact with Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) to regulate cellular survival and the unfolded protein response (UPR). MANF is a unique neurotrophic factor primarily localized in the endoplasmic reticulum (ER) lumen that is secreted in response to ER stress, a condition central to the pathogenesis of many neurodegenerative and metabolic diseases. Its primary intracellular partner is the UPR sensor IRE1alpha (Inositol-requiring enzyme 1 alpha); MANF binds to the luminal domain of IRE1alpha to inhibit its oligomerization and phosphorylation, thereby attenuating pro-apoptotic signaling. Extracellularly, MANF interacts with receptors such as Neuroplastin (NTPN) to suppress inflammatory NF-kappaB signaling and the KDEL receptor (KDELR) to facilitate its own cellular uptake and retrograde transport. Additionally, MANF acts as a cofactor for the major ER chaperone GRP78 (BiP), assisting in protein folding homeostasis. This interactome is a significant therapeutic target for conditions like Parkinson's disease and diabetes, where modulating these molecular partnerships can preserve cell viability and function.

Other names

MANF-related molecular partnersMANF interactomeMANF-interacting proteinsMANF conserved interactomeMANF/CDNF interactome

MANF and its partners regulate the unfolded protein response (UPR) by inhibiting the oligomerization and phosphorylation of IRE1alpha, acting as cofactors for GRP78-mediated protein folding, and binding to cell surface receptors like Neuroplastin to inhibit NF-kappaB signaling.