The unhindered lateral mobility of a rhomboid intramembrane protease enables synapse remodelling

Synapses must maintain their stable molecular organisation while retaining the capacity to remodel in response to changing demands. In order to flexibly change synaptic strength, the abundance of trans-synaptic adhesion complexes needs to be modulated, yet how this is achieved is poorly understood. Here, we identify the rhomboid protease RHBDL2 as a membrane-immersed regulator of adhesion complexes that enables mature synapses to adjust their composition both at steady-state and during their active restructuring. To do so, RHBDL2 possesses unrestrained diffusion properties that enable it to constitutively scan the neuronal surface and remove available adhesion molecules through irreversible cleavage of their transmembrane domains. Demonstrating its physiological importance, diffusion-dependent membrane surveillance by RHBDL2 is required for synapses to undergo remodelling during long term depression. Overall, we reveal a mechanism that cells use to preserve functional signalling complexes in membranes while selectively removing dispensable transmembrane proteins.