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Submitted on August 17, 2004
Accepted on February 23, 2005
decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt
Signal Transduction, Department of Internal Medicine (E.A.M., R.R.A., T.R., S.S.C., T.G.), and Department of Cell Biology and Human Anatomy (E.A.M., K.L.E.), School of Medicine, University of California, Davis, California 95616
* To whom correspondence should be addressed. E-mail: ttgoldkorn{at}ucdavis.edu.
Tumor necrosis factor-
(TNF-) is a mediator of insulin resistance in sepsis, obesity and type 2 diabetes, and is known to impair insulin signaling in adipocytes. Akt (protein kinase B) is a crucial signaling mediator for insulin. In the present study, we examined the posttranslational mechanisms by which short-term (< 6 h) exposure of 3T3-L1 adipocytes to TNF- decreases Akt levels. TNF- treatment both increased the ubiquitination of Akt and decreased its protein level. The decrease in protein was associated with the presence of an (immuno-reactive) Akt fragment following TNF- treatment, indicative of Akt cleavage. The broad-spectrum caspase inhibitor Boc-D-FMK markedly suppressed these effects of TNF-. The caspase-6 inhibitor Z-VEID-FMK potently suppressed Akt ubiquitination, degradation and fragment formation, whereas, the proteasome inhibitor MG132 modestly attenuated the decline in Akt levels. Exposure to TNF- also enhanced the association of Akt with an E3 ligase activity. Adipocytes preexposed to either TNF- for 5 h and then stimulated with insulin for 30 min exhibited decreased levels of Akt, phosphorylated Akt, as well as phosphorylated Mdm2 which is a known direct substrate of Akt, and glucose uptake. Caspase inhibition attenuated these inhibitory effects of TNF-. Collectively, our results suggest that TNF- induces the caspase-dependent degradation of Akt via the cleavage and ubiquitination of Akt, which results in its degradation through the 26S proteasome. Furthermore, the caspase- and proteasome-mediated degradation of Akt due to TNF- exposure leads to impaired Akt-dependent insulin signaling in adipocytes. These findings expand the mechanism by which TNF- impairs insulin signaling.
•
AKT •
UBIQUITIN •
CASPASE •
DEGRADATION •
INSULIN
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