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The pentose phosphate pathway (PPP) plays an essential role in cell proliferation via production of NADPH.Smooth muscle (SM) 22a protein is involved in the regulation of vascular smooth muscle cell (VSMC) phenotypes.To identify the relationship between NADPH production and SM22α activity in the development and progression of vascular diseases, glucose-6-phosphate dehydrogenase (G6PD) activity was measured using a specific kit, and apoptosis was determined by TUNEL assay.We showed that the expression and activity of G6PD is promoted in PDGF-BB-induced proliferative VSMCs.PDGF-BB induced G6PD membrane translocation and activation in a SM22α K21 ubiquitination-dependent manner.The ubiquitinated SM22α interacted with G6PD, and mediated G6PD membrane translocation.Furthermore, we found that TNF receptor associated factor (TRAF) 6 mediated SM22α K21 ubiquitination in a K63-linked manner upon PDGF-BB stimulation.Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, parallel with reduced SM22cα K21 ubiquitination.