Follicular lymphoma-associated mutations in the V-ATPase chaperone Vma21 activate autophagy by dysfunctional V-ATPase assembly.

ABSTRACT: A significant number of follicular lymphoma patients display recurrent mutations in subunits and regulators of the vacuolar-type H⁺-translocating ATPase (V-ATPase). Past studies focusing on the role of these mutations highlighted essential functions of macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we demonstrate novel results understanding the role of the follicular lymphoma-associated hotspot mutation VMA21p.93X, which corresponds to Vma21[Δ66-77] in S. cerevisiae cells. We find that V-ATPase assembly is affected by the Vma21[Δ66-77] mutation, shown by decreased vacuolar levels of V₀ subunits as well as a Vph1 stability assay. In addition, we report that vacuolar levels of histidine, lysine and arginine are significantly reduced in Vma21[Δ66-77] mutant cells. These results deepen the current understanding on the mechanism of how autophagy is activated by these mutations in follicular lymphoma.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC10309153 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature