Cell Biology and Genetics Track — David Katzmann Lab
“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).
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