TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

Abstract

Recently, glucose metabolism has been highlighted as part of a novel mechanism involved in the complex regulation Molecular Medicine© 2015 American Heart Association, Inc. Objective: To identify the relationship between dihydronicotinamide adenine dinucleotide phosphate production and SM22α activity in the development and progression of vascular diseases. Methods and Results:We showed that the expression and activity of glucose-6-phosphate dehydrogenase (G6PD)are promoted in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. PDGF-BB induced G6PD membrane translocation and activation in an SM22α K21 ubiquitination-dependent manner. Specifically, the ubiquitinated SM22α interacted with G6PD and mediated G6PD membrane translocation. Furthermore, we found that tumor necrosis factor receptor-associated factor (TRAF) 6 mediated SM22α K21 ubiquitination in a K63-linked manner on PDGF-BB stimulation. Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, in parallel with reduced SM22α K21 ubiquitination. Elevated levels of activated G6PD consequent to PDGF-BB induction led to increased dihydronicotinamide adenine dinucleotide phosphate generation through stimulation of the pentose phosphate pathway, which enhanced VSMC viability and reduced apoptosis in vivo and in vitro via glutathione homeostasis. Conclusions:We provide evidence that TRAF6-induced SM22α ubiquitination maintains VSMC survival through increased G6PD activity and dihydronicotinamide adenine dinucleotide phosphate production. The TRAF6-SM22α-G6PD pathway is a novel mechanism underlying the association between glucose metabolism and VSMC survival, which is beneficial for vascular repair after injury but facilitates atherosclerotic plaque stability.

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

“…Upon exposure to irradiation, ATM kinase promotes G6PD activity to enhance nucleotide production33. Post-translationally, G6PD is modified by lysine acetylation, phosphorylation, ubiquitination and O-GlcNAcylation34353637. We previously found that G6PD is deacetylated and activated by SIRT238, which led us to explore the possibility of targeting SIRT2 to suppress G6PD and leukaemia394041.…”

SM22α inhibits lamellipodium formation and migration via Ras-Arp2/3 signaling in synthetic VSMCs

“…The majority of intimal SMCs within atherosclerotic lesions are derived from resident medial SMCs that undergo phenotypic modulation and migration into the intima, where they proliferate (18,34). PDGF-BB-treated VSMCs display increased activity of migration and proliferation, accompanied with decreased SM22␣ expression (8,18,21,35), leading to the speculation of a negative correlation between VSMC migration and SM22␣ expression. The present study provided evidence that overexpression of SM22␣ inhib-C765 SM22␣ IN VSMC LAMELLIPODIUM FORMATION its PDGF-BB-induced cell migration in synthetic VSMCs and that disruption of SM22␣ promotes migratory responses after artery ligation.…”

Malic enzyme 2 as a potential therapeutic drug target for cancer

“…NADPH works as cellular reducing agent and it plays a critical function in maintaining redox balance and biosynthesis of macromolecules. NADPH is generated by metabolic enzymes such as 6‐phosphogluconate dehydrogenase (6PGD) , glucose‐6‐phosphate dehydrogenase (G6PD) of the pentose phosphate pathway (PPP) , isocitrate dehydrogenases (IDHs) , and malic enzymes (MEs). These enzymes which are associated with the production of NADPH are currently reported as potential therapeutic targets for cancer .…”