Dores et al. reveal how a G protein–coupled receptor (GPCR) can be sorted to multivesicular bodies (MVBs) and lysosomes without being ubiquitinated.
PAR1 is a GPCR for the protease thrombin. Like other GPCRs, activated PAR1 is downregulated by its internalization and transport to lysosomes for degradation. Unlike other receptors, however, PAR1 doesn't have to be ubiquitinated to move to lysosomes, and ubiquitin-binding components of the ESCRT complexes—which sort GPCRs and other cargo into intralumenal vesicles (ILVs) within MVBs en route to lysosomes—aren't required for PAR1 trafficking.
Dores et al. found that, nevertheless, PAR1 passed through ILVs on its way to lysosomes and that a PAR1 mutant that couldn't be ubiquitinated took an identical route. The sorting of PAR1 into ILVs required CHMP4, a core component of the ESCRT-III complex, which releases vesicles into the interior of MVBs. PAR1 sorting also depended on ALIX, a CHMP4-interacting protein that bound to a conserved motif in PAR1, thereby linking the receptor to the ESCRT-III sorting machinery.
ALIX links viral proteins to the ESCRT-III complex during viral budding, but the protein hasn't been implicated in mammalian receptor trafficking until now. Several other GPCRs have the same ALIX-binding motif as PAR1. The interaction with ALIX allows PAR1 to bypass the usual requirements for ubiquitination and ubiquitin-binding ESCRT subunits. Yet PAR1 is still ubiquitinated in response to thrombin. Senior author JoAnn Trejo now wants to investigate the function of this modification and to understand why PAR1 uses a sorting mechanism different from that used by most other GPCRs.
