Yoshimura et al. identify a family of proteins that activate different Rab GTPases at specific cell locations to control a variety of membrane trafficking events.
There are 63 human Rabs that control membrane transport, but the guanine nucleotide exchange factors (GEFs) that switch each of them on at specific times and places are unknown for most family members. The handful of Rab GEFs that have been identified are largely unrelated to one another, although a GEF for Rab3 contains a sequence motif found in several other proteins involved in membrane trafficking.
Yoshimura et al. tested the 17 human proteins with this motif—known as a DENN domain—for their ability to activate Rab proteins. Each DENN protein stimulated distinct Rabs involved in different trafficking routes. DENND4, for example, activated Rab10, a key regulator of polarized sorting to the basolateral surface of epithelial cells. DENND2A was found on actin filaments and regulated Rab9's function in transport between late endosomes and the Golgi. In all, the 17 DENN proteins were found to control 10 different Rabs with the DENN domain itself critical for the nucleotide exchange process.
Some of the DENN proteins or their Rab targets are altered in human disease, so the findings should help researchers understand how Rab misregulation contributes to pathogenesis. Yet many Rabs still have no known activator, something senior author Francis Barr hopes to rectify by examining the potential GEF activity of other gene families associated with membrane trafficking.