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

Abstract

Sequence similarity underlies most protein annotation, yet many functions remain hidden beyond detectable homology^1-3. By mining millions of AlphaFold2 models^4,5, 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.