Journal: ACS Chemical Neuroscience

Article Title: Improving Proteostasis of Trafficking-Deficient GABA A Receptor Variants by Activating IRE1

doi: 10.1021/acschemneuro.5c00227

Figure Lengend Snippet: Mechanism of action of IRE1/XBP1s activators on enhancing GABA A R variant proteostasis. Certain GABA A R variants misfold in the ER and undergo excessive ER-associated degradation (ERAD), leading to their trafficking deficiency to the plasma membrane. IRE1/XBP1s activators enhance the ER folding capacity to promote the folding of a variant by increasing the interaction between the variant and BiP, a pro-folding chaperone, and further promote the assembly into pentameric receptors in the ER membrane. In addition, such IRE1/XBP1s activators inhibit the ERAD of the variant by decreasing the interaction between the variant and Grp94, Hrd1-Sel1L, and VCP, known ERAD factors for GABA A Rs. Consequently, IRE1/XBP1s activators enhance the anterograde trafficking of the variant to the plasma membrane by increasing the interaction between the variant and LMAN1. The receptor variant is also stabilized after reaching the plasma membrane.

Article Snippet: The rabbit polyclonal anti-Grp94 antibody (#14700-1-AP, 1:250) was obtained from Proteintech.

Techniques: Variant Assay, Clinical Proteomics, Membrane