GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gas and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca2+-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca2+-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM impairs tumor growth in vitro, suggesting functions of ESYT1 beyond the interaction with GPR133. Our findings suggest a novel mechanism for modulation of GPR133 signaling by increased cytosolic Ca2+, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.

Objectives Asian Americans (AAs) experience a complex and growing non-communicable disease burden linked with dietary behaviors. Dietary norms, which significantly contribute to eating behaviors, face a complex set of Western and Asian socio-ecological influences in AA communities. However, little is known of how dietary norms (such as definitions of a “healthy diet”) are transmitted, intersect, and differ in a multigenerational family environment. Methods AA young adults and family members were recruited to participate in dyadic, 60-minute Zoom interviews (Jun - Dec 2021). Young adults and family members were interviewed separately on their respective eating behaviors, including perceived definition of a healthy diet. Recordings were inductively analyzed to identify themes related to different facets of a conceptualized healthy diet. Results A total of 41 AAs were interviewed (76% female, 61% US-born, age 19–69), including 20 young adults and 21 family members (10 parents, 9 siblings, 2 cousins). Diet healthfulness was defined in three dimensions: types of food, cooking methods, and intersection of diet with holistic wellbeing. Young adults consistently emphasized the role of their parents in shaping their idea of a healthy diet, particularly Asian-specific conceptualizations of balance (e.g., “yeet hay”). However, while these ideas were particularly influential among older participants, younger participants also emphasized the intersection of diet with emotional and spiritual well-being. Both stressed cooking methods as indicators of healthfulness. While a “healthy diet” was conceptualized through intake of food groups such as fruits, vegetables, and proteins, foreign-born and older participants put a larger emphasis on dietary restrictions (e.g., completely cutting out food groups, such as fast food), while US-born and younger participants stressed enjoying foods in moderation. Conclusions The differential understanding and impact of AA norms related to diet healthfulness highlights the need for a disaggregated understanding of dietary attitudes and behaviors in health-based interventions for AAs of different generations, particularly family-based programs. Findings call for future mixed-methods research to explore the complex dietary norms identified. Funding Sources South Asian Health and Research Group (SAHARA).