Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that activates the downstream MAPKs, c-Jun N-terminal kinase (JNK) and p38. ASK1 is activated by various types of stress, such as oxidative stress, endoplasmic reticulum stress, and infection, and regulates various cellular functions. Recently, it has been reported that ASK1 is associated with various diseases induced by oxidative stress. In this review, we introduce recent findings of the regulatory mechanisms of ASK1 and the oxidative stress-induced diseases mediated by the ASK1 signaling pathway.

Figure 1

Mechanisms of ROS-induced ASK1 activation. Thioredoxin (Trx), a negative regulator of ASK1, is dissociated from the N-terminal region of ASK1 in response to ROS. Subsequently, TRAF2 and TRAF6 are recruited, thereby fully activating ASK1. The ROS-induced activation of ASK1 results in its ubiquitination and proteasome-dependent degradation. USP9X negatively regulates ASK1 degradation by deubiquitination, leading to the sustained activation of ASK1. CCC: C-terminal coiled-coil domain; NCC: N-terminal coiled-coil domain.