Abstract 2458 A Novel GPCR-like Protein, SD1, Regulates Cell Morphology, Lysosomal Dynamics, and Intercellular Communication

Using millions of AlphaFold2 (AF2) predictions, our lab recently identified two families of "super dark" seven-transmembrane proteins (7TMPs) in humans that resemble but lack sequence similarity to known G protein-coupled receptors (GPCRs).These superdark families have some GPCR-like characteristics, including b-arrestin recruitment and G protein receptor kinase (GRK) phosphorylation.Furthermore, we show that one superdark, SD1, recruits and regulates mTOR signaling.Unlike most GPCRs, SD1 resides in intracellular vesicles that rapidly traverse the cytoskeleton via microtubules.Unlike most GPCRs, SD1 resides in intracellular vesicles that rapidly traverse the cytoskeleton via microtubules/actin and self-disseminate via vesicular scission.We further show that SD1 vesicles are highly enriched in growing cellular projections and appear to drive and maintain the formation of tunneling nanotubes (TNTs) through which they travel and assist intercellular lysosome transfer.Lastly, we show that SD1 has archaeal origins and fully rescues the vacuolar defects caused by deleting its yeast homolog.Together, these findings mark significant breakthroughs in illuminating dark proteins, mTOR signaling biology, and intercellular communication.