biostudies-literatureUnknown28(3)Krassikova LVetenskapsrådetCancerfondenCancer cells undergo complex metabolic alterations. The mechanisms underlying the tuning of cancer metabolism are under active investigation. Here, we identify the uncharacterized deubiquitinase JOSD2 as a positive regulator of cancer cell proliferation by displaying comprehensive effects on glucose catabolism. We found that JOSD2 directly controls a metabolic enzyme complex that includes Aldolase A, Phosphofructokinase-1 and Phosphoglycerate dehydrogenase, in vitro and in vivo. Further, JOSD2 expression, but not a catalytically inactive mutant, deubiquitinates and stabilizes the enzyme complex, thereby enhancing their activities and the glycolytic rate. This represents a selective JOSD2 feature that is not shared among other Machado-Joseph disease DUBs or observed in nontransformed cells.Cell death and differentiation1091-1109https://www.ebi.ac.uk/biostudies/studies/S-EPMC7937685biostudies-literatureThe deubiquitinase JOSD2 is a positive regulator of glucose metabolism.PMC7937685Nagarajan DQueiroz ALSamakidis EVakifahmetoglu-Norberg HNorberg EZhang BKrassikova LKacal MfalseThe deubiquitinase JOSD2 is a positive regulator of glucose metabolism.Cancer cells undergo complex metabolic alterations. The mechanisms underlying the tuning of cancer metabolism are under active investigation. Here, we identify the uncharacterized deubiquitinase JOSD2 as a positive regulator of cancer cell proliferation by displaying comprehensive effects on glucose catabolism. We found that JOSD2 directly controls a metabolic enzyme complex that includes Aldolase A, Phosphofructokinase-1 and Phosphoglycerate dehydrogenase, in vitro and in vivo. Further, JOSD2 expression, but not a catalytically inactive mutant, deubiquitinates and stabilizes the enzyme complex, thereby enhancing their activities and the glycolytic rate. This represents a selective JOSD2 feature that is not shared among other Machado-Joseph disease DUBs or observed in nontransformed cells.2021-01-01T00:00:00Z2021 Mar2026-04-08T17:57:56.907Z2025-04-05T22:21:33.806ZS-EPMC79376853308251410.1038/s41418-020-00639-1