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

EMBO Rep. 2016 Jun;17(6):823-41. doi: 10.15252/embr.201541382. Epub 2016 Apr 13.

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 GTPase 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.

Keywords: BHD syndrome; RILP; Rab34; folliculin; lysosome.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Estrone / pharmacology*
  • Gene Expression
  • Golgi Apparatus / metabolism
  • Humans
  • Intracellular Membranes / metabolism
  • Lysosomes / metabolism
  • Nuclear Proteins
  • Protein Binding / drug effects
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Recombinant Proteins
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • FLCN protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RAB34 protein, human
  • RILP protein, human
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Estrone
  • rab GTP-Binding Proteins