Folliculin directs the formation of a Rab34– RILP complex to control the nutrient‐dependent dynamic distribution of lysosomes

Abstract

The spatial distribution of lysosomes is important for their function and is, in part, controlled by cellular nutrient status. Here, we show that the lysosome associated Birt–Hoge–Dubé ( BHD ) syndrome renal tumour suppressor folliculin ( FLCN ) regulates this process. FLCN promotes the peri‐nuclear clustering of lysosomes following serum and amino acid withdrawal and is supported by the predominantly Golgi‐associated small GTP ase Rab34. Rab34‐positive peri‐nuclear membranes contact lysosomes and cause a reduction in lysosome motility and knockdown of FLCN inhibits Rab34‐induced peri‐nuclear lysosome clustering. FLCN interacts directly via its C‐terminal DENN domain with the Rab34 effector RILP . Using purified recombinant proteins, we show that the FLCN ‐ DENN domain does not act as a GEF for Rab34, but rather, loads active Rab34 onto RILP . We propose a model whereby starvation‐induced FLCN association with lysosomes drives the formation of contact sites between lysosomes and Rab34‐positive peri‐nuclear membranes that restrict lysosome motility and thus promote their retention in this region of the cell. image This study shows how the renal tumour suppressor folliculin couples the lysosomal nutrient signaling network to the cellular machinery that controls the intracellular distribution of the organelle itself. The renal tumour suppressor folliculin co‐operates with Rab34 to control lysosome distribution in response to nutrient starvation. Rab34‐positive perinuclear membranes contact lysosomes. The folliculin‐DENN domain interacts directly with RILP and loads it with active Rab34.