Cell Biology and Genetics Track - David Katzmann Lab
Vta1 regulates ESCRT III release from the endosomal membrane through activating Vps4. ESCRT III subunits (Snf7, Vps20, Vps2 and Vps24) assemble on the endosomal membrane and must be dissociated by the AAA-ATPase Vps4 to permit MVB sorting to proceed. Vta1 binds to Vps4 and stimulates the recycling of the ESCRT III subunits. Biochemical analysis identified how Vta1 stimulates the Vps4 ATPase cycle (inset). Vps4 is a dimer in the absence of ATP. Upon binding ATP, Vps4 homo-oligomerizes into a higher order complex, which is then competent to hydrolyze ATP. Vta1 promotes this Vps4 oligomerization and can stimulate Vps4 ATPase activity. By stimulating Vps4 ATPase activity and ESCRT III recycling, Vta1 regulates flux through the MVB pathway.
“Down-regulation” of activated receptors is crucial to prevent aberrant signaling, which can contribute to uncontrolled cellular proliferation. Internalized activated receptors enter the intra-lumenal vesicles within multivesicular bodies (MVB) en route to degradation in the lysosome. Hence the MVB pathway plays an essential role in regulating cell surface protein composition as well as in other cellular functions. Characterization of the class E Vps or Endosomal Sorting Complex Required for Transport (ESCRT) proteins has provided insights into the intricate mechanisms governing this process. Our laboratory is interested in further understating this complicated process through elucidating factors that regulate flux through the MVB pathway.
My work has focused on a regulator of the class E protein Vps4. This belongs to a family of proteins called AAA-ATPases that are involved in many cellular activities including dissociation of protein complexes such as SNAREs, microtubules, and ESCRTs. Vps4 acts late in the MVB sorting reaction to recycle the ESCRT components. By utilizing biochemical and genetic analyses in the model organism Saccharomyces cerevisiae, we have demonstrated that Vta1 acts as a positive modulator of Vps4 both in vivo and in vitro. Vta1 activates Vps4 by promoting Vps4 oligomerization and stimulates its ATPase activity through a carboxyl-terminal VSL (Vta1/SBP1/Lip5) region. Moreover, we have demonstrated that the human homolog of Vta1, SBP1, is also capable of binding to Vps4 and stimulating Vps4 ATPase activity via the SBP1 VSL region. Therefore, we concluded that Vta1 homologs regulate Vps4-dependent disassembly of ESCRTs from yeast to man.
This work identified the first known regulator of flux through the MVB pathway and was published in the Journal of Cell Biology (1).
- Azmi I, Davies B, Dimaano C, Payne J, Eckert D, Babst M, Katzmann DJ. Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a conserved VSL region in Vta1. J Cell Biol 2006; 172:705-717.