Blümer et al. reveal that Rab GTPases are targeted to the correct intracellular membrane by the guanine nucleotide exchange factors (GEFs) that activate them.
There are over 60 Rabs in human cells that regulate different vesicle trafficking events by localizing to specific membrane compartments. In their inactive, GDP-bound form, Rabs are maintained in the cytosol by chaperones called GDP dissociation inhibitors (GDIs). When activated by specific GEFs, Rabs dissociate from GDIs and bind to membranes via lipid groups attached to their C termini. But how Rabs localize to particular membranes is unclear. Blümer et al. wondered whether RabGEFs might be important for targeting, as well as activating, the GTPase family.
To test this idea, the researchers devised a way to inducibly mislocalize RabGEFs. When Rabex-5, a GEF that usually activates Rab5 on early endosomes, was redirected to mitochondria, it immediately spurred the recruitment of Rab5—but not other Rab GTPases—to mitochondrial membranes. Rabex-5’s GEF domain was sufficient to target Rab5, and Rabex-5 mutants with reduced GEF activity were less efficient at relocalizing the GTPase.
Blümer et al. showed that two other GEFs—Rabin8 and DrrA—were also capable of recruiting their cognate Rabs to specific membranes. The authors now want to test the targeting function of additional RabGEFs and, because many Rabs don’t yet have a known activator, to identify new members of this heterogeneous protein family.
Text by Ben Short