SEPHS2 deficiency reprograms glucose metabolism to activate the pentose phosphate pathway by stabilizing PCK1 through NAD+

We found that SEPHS2 knockout inhibits oxidative phosphorylation (OXPHOS), but has no effect on glycolysis, as indicated by an seahorse assay. SEPHS2 loss redirects more glucose to the pentose phosphate pathway (PPP).

Mechanistically, SEPHS2 knockout elevates NAD+ levels, which are essential for Sirtuin activity. The increase in the activity of SIRT2 leads to deacetylation of PCK1, a posttranslational modification required to prevent PCK1’s ubiquitination and subsequent degradation. Thus, SEPHS2 knockout stabilizes PCK1 by reducing its ubiquitination.