Sestrins Activate Nrf2 by Promoting p62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver Damage

Abstract

Sestrins (Sesns) protect cells from oxidative stress. The mechanism underlying the antioxidant effect of Sesns has remained unknown, however. The Nrf2-Keap1 pathway provides cellular defense against oxidative stress by controlling the expression of antioxidant enzymes. We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62-dependent autophagic degradation of Keap1. Sesn2 was upregulated in the liver of mice subjected to fasting or subsequent refeeding with a high-carbohydrate, fat-free diet, whereas only refeeding promoted Keap1 degradation and Nrf2 activation, because only refeeding induced p62 expression. Ablation of Sesn2 blocked Keap1 degradation and Nrf2 activation induced by refeeding and thereby increased the susceptibility of the liver to oxidative damage resulting from the acute stimulation of lipogenesis associated with refeeding.

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

“…One is by upregulating NFE2L2 (nuclear factor, erythroid derived 2, like 2) signaling and thereby promoting the expression of genes for antioxidant enzymes. 29 The other is by blocking MTOR activation, which results in ROS accumulation. 23,24,46 The SESN2-promoted mitophagy in our study provides the third pathway for SESN2 to suppress ROS accumulation.…”

“…Under oxidative stress, SESN2 serves as an adapter protein that mediates the interaction between SQSTM1 and KEAP1, which results in the autophagic degradation of KEAP1. 29 In a recent study, SESN2 was shown to also induce autophagic degradation of SQSTM1 by promoting ULK1-mediated SQSTM1 phosphorylation via its interaction with ULK1 and SQSTM1. 38 Based on these data and our result that SESN2 induces mitophagy by mediating SQSTM1 binding to ubiquitinated mitochondria via its interaction with SQSTM1, we speculate that SESN2 may be involved in SQSTM1-mediated autophagic degradation through its binding to SQSTM1 and/or SQSTM1 target proteins in response to various cellular stresses.…”

“…29,38 Several studies have revealed that signal-dependent phosphorylation of SQSTM1 at specific sites (Ser349, Ser351, Ser403) is critical to degradation of ubiquitinated proteins targeted by SQSTM1 by reinforcing interactions between them. 29,39,40 Therefore, we first examined the extent of phosphorylation of SQSTM1 at Ser349, Ser351, and Ser403 in Sesn2 C/C BMDMs in the absence or presence of stimulation. Therein, phosphorylation of SQSTM1 at Ser349 and Ser351, but not Ser403, increased upon stimulation (Fig.…”

“…24,27,28 In addition, SESN2 can induce autophagic degradation of KEAP1 (kelch-like ECH-associated protein 1) through association with SQSTM1 triggered by the acute lipogenic stimulus. 29 Furthermore, despite significant progress in understanding the function of SESN2 in metabolic pathways and diseases, the regulatory roles of SESN2 in immune responses and the mechanisms involved therein have not yet been revealed. Here, we demonstrate that bone marrow-derived macrophages (BMDMs) from sesn2 ¡/¡ mice displayed defective mitophagy upon immune stimulation, which resulted in hyperactivation of the NLRP3 inflammasome and increased mortality from sepsis.…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…Sestrin (Sesn2) induction invokes p62, a competitive antagonist of Keap1, which mimics the binding of the ETGE motif of Nrf2 to the kelch domain, but only under overexpressed conditions of Sesn2. Under normal conditions, p62 does not replace Nrf2 binding antagonistically because of the weak binding it projects on Keap1 as compared to the ETGE motif (Bae et al 2013). …”