A GluN2B disease-associated variant promotes degradation of NMDA receptors via autophagy
N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission and their pathogenic variants can lead to proteostasis defects and thus neurological diseases. However, how the proteostasis network degrades pathogenic variants is not well understood. Here, we demonstrated that the R519Q GluN2B variant is retained in the endoplasmic reticulum (ER) and fails to traffic to the surface to form functional NMDARs. Pharmacological and genetic inhibition of autophagy results in the accumulation of this variant, indicating that it is degraded by the autophagy-lysosomal proteolysis pathway. Since GluN2B has a cytosolic LIR motif, which can interact with cytosolic autophagy machinery, we demonstrated that disrupting this LIR motif impairs the autophagic clearance of this variant. Additionally, the R519Q variant is recognized by ER-phagy receptors, including CCPG1 and RTN3L. Our result provides the molecular mechanism for the degradation of NMDAR variants and identifies a pathway for targeted therapeutic intervention for neurological disorders with dysfunctional NMDARs. SummaryNMDA receptors are essential for excitatory neurotransmission and their proteostasis defects lead to neurological diseases. Benske et al. report that pathogenic R519Q variants predispose GluN2B subunits to degradation and clearance by the autophagy-lysosomal pathway.