Role of Varp, a Rab21 exchange factor and TI‐VAMP/VAMP7 partner, in neurite growth

Abstract

The vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP/VAMP7) was previously shown to mediate an exocytic pathway involved in neurite growth, but its regulation is still largely unknown. Here we show that TI-VAMP interacts with the Vps9 domain and ankyrin-repeat-containing protein (Varp), a guanine nucleotide exchange factor (GEF) of the small GTPase Rab21, through a specific domain herein called the interacting domain (ID). Varp, TI-VAMP and Rab21 co-localize in the perinuclear region of differentiating hippocampal neurons and transiently in transport vesicles in the shaft of neurites. Silencing the expression of Varp by RNA interference or expressing ID or a form of Varp deprived of its Vps9 domain impairs neurite growth. Furthermore, the mutant form of Rab21, defective in GTP hydrolysis, enhances neurite growth. We conclude that Varp is a positive regulator of neurite growth through both its GEF activity and its interaction with TI-VAMP.

Rabex-5 Protein Regulates Dendritic Localization of Small GTPase Rab17 and Neurite Morphogenesis in Hippocampal Neurons

“…Although involvement of two other target Rabs, Rab21 and Rab22, in neurite outgrowth of PC12 cells has been reported (41,43), knockdown of neither Rab21 nor Rab22A/B with specific shRNAs had virtually any effect on neurite morphogenesis under our experimental conditions (Fig. 8, E-H).…”

“…This discrepancy may be attributable to the difference in assay protocols, 4 DIV in Ref. 43 and 11 DIV in this study. We speculate that Rab21 and Varp function at an early stage of axon outgrowth.…”

“…reported that knockdown of Varp, a Rab21-specific GEF (45), in hippocampal neurons reduced total axon length at 4 DIV (43). This discrepancy may be attributable to the difference in assay protocols, 4 DIV in Ref.…”

Role of tetanus neurotoxin insensitive vesicle-associated membrane protein in membrane domains transport and homeostasis

“…31,39 Our time-lapse imaging experiment clearly indicates that GPIanchored proteins are to a certain extent in VAMP7-positive vesicles following their exit from the TGN, suggesting co-transport outbound the Golgi. In addition, Varp interacts with Vps29, a subunit of the retromer, and both are involved in the transport of the glucose transporter GLUT1 to the PM whereas VAMP7 is involved in exocytosis of both GLUT1 and GLUT4.…”

Un réseau moléculaire pour le transport des vésicules du centre à la périphérie cellulaire

“…Ce trafic est aussi nécessaire à la migration et au guidage des neurones et des cellules épi-théliales [3,4] [7]. Nous avons montré que TI-VAMP interagit avec VARP (Vps9 domain and ankyrin repeats containing protein), un facteur d'échange de la petite GTPase RAB21 [8]. Notre identification de l'interaction de TI-VAMP avec Varp a récemment été complétée par la structure des domaines d'interaction [9].…”