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The deubiquitinase JOSD2 is a positive regulator of glucose metabolism
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-10-20 , DOI: 10.1038/s41418-020-00639-1
Lyudmila Krassikova 1 , Boxi Zhang 1 , Divya Nagarajan 1 , André Lima Queiroz 1, 2 , Merve Kacal 1 , Evangelos Samakidis 1 , Helin Vakifahmetoglu-Norberg 1 , Erik Norberg 1
Affiliation  

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. JOSD2 deficiency displays cytostatic effects and reduces glycolysis in a broad spectrum of tumor cells of distinct origin and its expression correlates with poor prognosis in non-small cell lung cancer. Overall, our study provides evidence for a previously unknown biological mechanism in which JOSD2 integrates glucose and serine metabolism with potential therapeutic implications.

更新日期:2020-10-20
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