The Endoplasmic Reticulum Membrane Complex Promotes Proteostasis of GABAAReceptors

ABSTRACT The endoplasmic reticulum membrane complex (EMC) plays a critical role in the biogenesis of tail-anchored and a subset of multi-pass membrane proteins in the endoplasmic reticulum. However, due to the nearly exclusive expression of neurotransmitter-gated ion channels in the central nervous system, the role of the EMC in their biogenesis is not well understood. In this study, we demonstrated that the EMC positively regulates the surface trafficking and thus function of endogenous γ-aminobutyric acid (GABA A ) receptors, the primary inhibitory ion channels in the mammalian brain. Further, among ten EMC subunits, EMC3 and EMC6 have the most prominent effects, indicating a subunit-specific contribution. EMC3 and EMC6 show endogenous interactions with major neuroreceptors, which depends on their transmembrane domains. Overexpression of EMC3 and EMC6 is sufficient to restore the function of epilepsy-associated GABA A receptor variants, suggesting that operating EMC has the potential to ameliorate neurological diseases associated with protein conformational defects. In brief The multi-subunit EMC serves as an insertase for a subset of membrane proteins and enables their biogenesis in the endoplasmic reticulum. However, the subunit-specific effect of the EMC on multi-pass neuroreceptors is not well understood. Whittsette et al. demonstrate that EMC3 and EMC6 interact with GABA A receptors and positively regulate their trafficking and function. Highlights EMC3 and EMC6 positively regulate the function of endogenous GABA A receptors. The EMC interacts with major endogenous neuroreceptors. The interaction between EMC and GABA A receptors depends on the EMC transmembrane domains. Overexpressing the EMC is sufficient to restore the function of pathogenic GABA A receptor variants.