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. Author manuscript; available in PMC: 2016 Nov 1.
Published in final edited form as: Free Radic Biol Med. 2015 Jun 27;88(0 0):108–146. doi: 10.1016/j.freeradbiomed.2015.06.021

Fig. 6.

Fig. 6

Model to explain the influence of Nrf2 on ROS-dependent ASK1 signaling. Intracellular levels of ROS represent a major regulator of ASK1 activity, as the kinase is repressed by reduced TXN but not by oxidized TXN. Transcription factor Nrf2 is predicted to modulate the sensitivity of ASK1 to ROS-dependent activation by its ability to increase GSH-based and TXN-based antioxidant systems, its ability to suppress production of ROS by modulating mitochondrial function, and possibly also its ability to repress the expression of NOX2 and NOX4. (A) In wild-type cells, Nrf2 negatively controls expression of NOX2 and NOX4, which produce ROS (top), with inhibition depicted by a blunt-headed arrow. Moreover, Nrf2 supports inactivation of ROS by increasing the expression of GCL (upper right-hand side), which catalyzes the rate-limiting step in GSH synthesis; by increasing the expression of GPX2, which reduces H2O2 using GSH as a cofactor; and by increasing the expression of PRDX1, which reduces H2O2 in a TXN-dependent manner (all are shown as arrows). Nrf2 maintains TXN in a reduced state by increasing expression of TXNRD1 and SRXN1 (middle and lower right-hand side), and TXN, TXNRD1, and SRXN1 contribute to the reduction of H2O2 by PRDX1 (Fig. 1). Last, by improving the efficiency of oxidative phosphorylation, Nrf2 limits production of ROS by mitochondria (left-hand side). (B) In Nrf2-null cells, production of ROS by NOX2 and NOX4 is increased (top), as is the production by mitochondria (left-hand side). In addition, the GSH-based antioxidant and TXN-based antioxidant systems are diminished through decreased expression of GPX2, GCL, PRDX1, TXNRD1, and SRXN1 that results from loss of Nrf2 (right-hand side). The increased production of ROS and the diminished antioxidant capacity in Nrf2-null cells combine to cause the redox status of TXN to be shifted toward oxidation, and therefore its inhibition of ASK1 will be less effective. As a consequence, the downstream p38MAPK and JNK kinases are more readily activated in Nrf2-null cells. Moreover, the increase in ROS in Nrf2-null cells will increase inhibition of MKP enzymes, and this will decrease the ability of the phosphatases to inhibit JNK and p38MAPK.