Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

Kanasaki, Keizo; Kawakita, Emi; Koya, Daisuke

When cells are exposed to oxidative stress, SQSTM1, known as the ubiquitin-binding protein p62 and an autophagosome cargo protein, is phosphorylated at Ser349. Phosphorylated form of SQSTM1 physically interacted with KEAP1, an adaptor of the ubiquitin ligase complex for Nrf2, with high affinity (Ueno and Komatsu, 2017) . The interaction between SQSTM1 and KEAP1 results in the suppression of KEAP1-driven ubiquitination of Nrf2; phosphorylated SQSTM1 and KEAP1 complexes are selectively degraded by autophagy (Ueno and Komatsu, 2017) . Thereafter, Nrf2 is stabilized, translocates into the nucleus, and induces the expression of various essential cytoprotective genes, such as NAD(P)H dehydrogenase quinone 1, glutathione S-transferase, glutamate-cysteine ligase catalytic subunit and heme oxygenase 1 (Jain et al., 2010; Komatsu et al., 2010; Lau et al., 2010; Taguchi et al., 2012; Ichimura et al., 2013) . Sestrin 2, also known as an intracellular leucine sensor that negatively regulates mTORC1 signaling, binds with the SQSTM1 and KEAP1 complexes and functions as a scaffold protein for the SQSTM1-mediated autophagy of KEAP1 (Bae et al., 2013) . Sestrin 2 is also induced under conditions of stress (Yang et al., 2014) ; Nrf2 activation might be regulated by selective autophagy under metabolic stress. Therefore, GLP-1-induced Nfr2 activation could be relevant to GLP-1-induced autophagy, but further study is needed. The association between GLP-1 and sestrin 2 has yet to be confirmed.