The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes.
The DENN domain is an evolutionarily ancient protein module. Mutations in the DENN domain cause developmental defects in plants and human diseases, yet the function of this common module is unknown. We now demonstrate that the connecdenn/DENND1A DENN domain functions as a guanine nucleotide exchange factor (GEF) for Rab35 to regulate endosomal membrane trafficking. Loss of Rab35 activity causes an enlargement of early endosomes and inhibits MHC class I recycling. Moreover, it prevents early endosomal recruitment of EHD1, a common component of tubules involved in endosomal cargo recycling. Our data reveal an enzymatic activity for a DENN domain and demonstrate that distinct Rab GTPases can recruit a common protein machinery to various sites within the endosomal network to establish cargo-selective recycling pathways.
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Patrick D
PD
Allaire
Andrea L
AL
Marat
Claudia
C
Dall'Armi
Gilbert
G
Di Paolo
Peter S
PS
McPherson
Brigitte
B
Ritter
D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002522:Chlorocebus aethiops; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D020662:Guanine Nucleotide Exchange Factors; C511183:RAB35 protein, human; D020691:rab GTP-Binding Proteins