Bruno Goud - The RAB6 GTPase, a master regulator of post-Golgi trafficking pathways
Channel: Institut des Hautes Études Scientifiques (IHÉS)
Date: 2018-03-26

The members of the RAB GTPase family (less than 60 proteins in man) are master regulators of intracellular transport and membrane trafficking in eukaryotic cells. RAB6 is one of the five ancestral RAB genes conserved from yeast to human. The RAB6 family comprises four proteins, named RAB6A, RAB6A’, RAB6B and RAB6C. The two ubiquitously expressed isoforms, RAB6A and A, are generated by alternative  splicing  of  the  same  gene  and  localize  to  the  Golgi  complex.  We  and  others  have established that RAB6 regulates several transport pathways at the level of this organelle.
Our recent work has focused on several aspects of RAB6 function:
-The  mechanisms  involved  in  the  fission  of  RAB6-positive  transport  carriers  from  Golgi/TGN (Trans-Golgi Network) membranes. We have previously shown that RAB6-Myosin IIA interaction is critical for this process [1].
Recently, we showed that the kinesin protein KIF20A is also involved in the fission process and serves to anchor RAB6 on Golgi/TGN membranes near microtubule (MT) nucleating sites. Our results suggest that the coupling between actin and MT cytoskeletons driven by  Myosin  II  and  KIF20A  ensures  the  spatial  coordination  between  the  fission  of  RAB6-positive 
vesicles from Golgi/TGN membranes and their exit along microtubules [2].
- The role of RAB6 in post-Golgi transport. Using the RUSH system
[3] and a variety of secretory cargos, including GPI-anchored proteins, TNF-alpha and Collagen-X, we found that RAB6 associates with post-Golgi vesicles containing all of these cargos. Depletion of RAB6 inhibits their arrival at the plasma  membrane.  These  results  suggest  that  RAB6  could  be  a  general  regulator  of  post-Golgi vesicles, possibly targeting secretory vesicles to defined exocytic sites on the cell surface [4].
-The role of RAB6 in cell lineages and tissues. We have generated mice with a conditional null allele of  RAB6A [5]. The  mice,  which  do  not  express  RAB6A  and  RAB6A’,  die  at  an  early  stage  of 
embryonic development (day 5.5), indicating that RAB6A is an essential gene. The phenotype of RAB6A-/- embryos is very similar tothat of beta-1 integrin null embryos. This result is consistent with the finding that a pool of inactive integrins follows the retrograde pathway regulated by RAB6 and that this pathway is critical for adhesion and persistent cell migration [6]. 
The RAB6 k/o mice were crossed with several mouse lines to deplete RAB6 in various tissues or cell lineages. We will present data illustrating that RAB6 fulfills different functions depending on the cell or tissue context.

References
1. Miserey-Lenkei et al. Nat. Cell Biol. 12, 645 (2010).
2. Miserey-Lenkei et al. Nat Commun. 8, 1254 (2017).
3. Boncompain et al. Nat. Methods 9, 493 (2012).
4. Miserey-Lenkei et al. submitted for publication.
5. Bardin et al. Biol. Cell 107, 427 (2015).
6. Shafaq-Zadah, Gomes-Santos, et al. Nat. Cell Biol. 18, 54 (2015).