LST1 promotes the assembly of a molecular machinery responsible for tunneling nanotube formation.

Carefully orchestrated intercellular communication is an essential prerequisite for the development of multicellular organisms. In recent years, tunneling nanotubes (TNT) have emerged as a novel and widespread mechanism of cell-cell communication. However, the molecular basis of their formation is still poorly understood. In the present study we report that the transmembrane MHC class III protein leukocyte specific transcript 1 (LST1) induces the formation of functional nanotubes and is required for endogenous nanotube generation. Mechanistically, we found that LST1 induces nanotube formation by recruiting the small GTPase RalA to the plasma membrane and promoting its interaction with the exocyst complex. Furthermore, we determined that LST1 recruits the actin-crosslinking protein filamin to the plasma membrane and interacts with M-Sec, myosin and myoferlin. These results allow us to suggest a molecular model for nanotube generation. In this proposal LST1 functions as a membrane scaffold mediating the assembly of a multimolecular complex, which controls the formation of functional nanotubes.