A Novel Interacting Protein SERP1 Regulates the N‐Linked Glycosylation and Function of GLP‐1 Receptor in the Liver

ABSTRACT Glucagon‐like peptide 1 (GLP‐1) exerts multiple effects on metabolism through its receptor, GLP‐1R, in the liver. Activation and transduction of GLP‐1R require complex interactions of largely unknown accessory proteins, and these processes are crucial to the response to endoplasmic reticulum (ER) stress. Using the membrane‐based split ubiquitin yeast two‐hybrid system (MYTH) and a human liver cDNA library, we obtained the human GLP‐1R interactome and identified SERP1 as a potential interacting protein based on its ability to stabilize membrane proteins and facilitate N‐linked glycosylation. GLP‐1R and SERP1 were co‐expressed in HEK‐293 cells, and their interaction was confirmed by co‐immunoprecipitation. We then found that overexpression of SERP1 could rescue GLP‐1R glycosylation after application of tunicamycin to block N‐linked glycosylation. SERP1 overexpression also attenuated exendin‐4‐stimulated cAMP accumulation and AMPK activation. However, the glycosylation and function of mutant GLP‐1R, in which all three sites for N‐linked glycosylation were mutated, were not increased with overexpression of SERP1. Moreover, as a GLP‐1R interactor, SERP1 could also partly reverse the accumulation of tunicamycin‐induced ER stress. Taken together, our findings identify a group of proteins that interact with GLP‐1R and show that one specific interacting protein, SERP1, has an important role in facilitating the glycosylation of GLP‐1R and rescuing its activities after ER stress induced by tunicamycin. J. Cell. Biochem. 118: 3616–3626, 2017. © 2017 Wiley Periodicals, Inc. SERP1, an accessory protein which be founded using the membrane‐based split‐ubiquitin yeast two hybrid (MYTH) system, can interact with GLP‐1R in the liver, it play important roles in its N‐glycosylation and activation and ameliorated ER stress by relieving Tunicamycin‐induced UPR.