TM184C is a GPCR-like regulator of intercellular exchange and autophagy

Sequence similarity underlies most protein annotation, yet many functions remain hidden beyond detectable homology1–3. By mining millions of AlphaFold2 models4,5, we identify two human families of ‘superdark’ seven-transmembrane proteins—TM184 and PRRT—with structural homology to G-protein-coupled receptors (GPCRs). These proteins exhibit hallmark GPCR activities, including β-arrestin recruitment and GPCR kinase (GRK)-dependent phosphorylation. Here we focus on TM184C—the most broadly expressed and evolutionarily conserved superdark GPCR-like protein, which localizes to highly dynamic intracellular vesicles rather than the plasma membrane. These vesicles move along microtubules, accumulate in cell projections and promote the formation of tunnelling nanotube- and tumour microtubule-like intercellular connections. These bridges mediate organelle sharing through a process that requires the TM184C C-terminal tail and its arrestin code motif6, linking GPCR-like β-arrestin and GRK regulation to vesicle function and intercellular connectivity. TM184C also constrains autophagic flux by limiting LC3B lipidation and autophagosome accumulation—a role that is deeply conserved, as human TM184C restores autophagic body homeostasis in yeast lacking its homologue, Hfl1. Together, these findings illustrate how structure-based protein discovery can illuminate the dark proteome and identify TM184C as an ancient GPCR-like regulator of autophagy, intercellular connectivity and material exchange. TM184C—an ancient G-protein-coupled receptor-like superdark protein involved in regulation of autophagy, intercellular connectivity and material exchange—underscores the promise of exploring the understudied human proteome and beyond.