Model of TRAF6 degradation by bortezomib-induced autophagy and its role in cell leukemia cell survival. (A) Under normal conditions, TRAF6 induces expression of survival genes. In addition, TRAF6 mediates the expression of PSMA1, an α-subunit of the proteasome. (B) Proteasome inhibition with bortezomib coincides with induction of autophagy, potentially due to ER stress of accumulated nondegraded proteins. TRAF6 is degraded by autophagic lysosomes, which can be blocked with the autophagy inhibitor 3-MA. Depletion of TRAF6 results in apoptotic cell death, in part by down-regulation of survival genes. In addition, loss of TRAF6 results in reduced PSMA1 expression and increased bortezomib sensitivity. α indicates the α-subunit; and β, the β-subunit.