Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation.
Nicole ScholzAnne-Kristin DahseMarguerite KemkemerAnne BormannGenevieve M AugerFernando Vieira ContrerasLucia F ErnstHauke StaakeMarek B KörnerMax BuhlanAmelie Meyer-MölckYin Kwan ChungBeatriz Blanco-RedondoFranziska KloseMohamed-Ali JarbouiDmitrij LjaschenkoMarina BiglTobias LangenhanPublished in: Nature (2023)
Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins 1 , a class of surface receptors poised for mechano-proteolytic activation 2-4 , including an evolutionarily conserved mechanism of cleavage 5-8 . However, so far there is no unifying explanation for why aGPCRs are autoproteolytically processed. Here we introduce a genetically encoded sensor system to detect the dissociation events of aGPCR heterodimers into their constituent N-terminal and C-terminal fragments (NTFs and CTFs, respectively). An NTF release sensor (NRS) of the neural latrophilin-type aGPCR Cirl (ADGRL) 9-11 , from Drosophila melanogaster, is stimulated by mechanical force. Cirl-NRS activation indicates that receptor dissociation occurs in neurons and cortex glial cells. The release of NTFs from cortex glial cells requires trans-interaction between Cirl and its ligand, the Toll-like receptor Tollo (Toll-8) 12 , on neural progenitor cells, whereas expressing Cirl and Tollo in cis suppresses dissociation of the aGPCR. This interaction is necessary to control the size of the neuroblast pool in the central nervous system. We conclude that receptor autoproteolysis enables non-cell-autonomous activities of aGPCRs, and that the dissociation of aGPCRs is controlled by their ligand expression profile and by mechanical force. The NRS system will be helpful in elucidating the physiological roles and signal modulators of aGPCRs, which constitute a large untapped reservoir of drug targets for cardiovascular, immune, neuropsychiatric and neoplastic diseases 13 .
Keyphrases
- toll like receptor
- electron transfer
- induced apoptosis
- cell cycle arrest
- drosophila melanogaster
- single molecule
- signaling pathway
- inflammatory response
- nuclear factor
- immune response
- cell death
- neuropathic pain
- cell proliferation
- small molecule
- spinal cord
- oxidative stress
- biofilm formation
- endoplasmic reticulum stress
- pseudomonas aeruginosa
- single cell
- spinal cord injury
- bone marrow
- candida albicans
- cell adhesion