The regulation of the autophagic network and its implications for human disease

Abstract

Autophagy has attracted a lot of attention in recent years. More and more proteins and signaling pathways have been discovered that somehow feed into the autophagy regulatory pathways. Regulation of autophagy is complex and condition-specific, and in several diseases, autophagic fluxes are changed. Here, we review the most well-established concepts in this field as well as the reported signaling pathways or components which steer the autophagy machinery. Furthermore, we will highlight how autophagic fluxes are changed in various diseases either as cause for or as response to deal with an altered cellular homeostasis and how modulation of autophagy might be used as potential therapy for such diseases.

Keywords: ATGs; Autophagy; FOXO1; HSF1; Heat Shock Proteins (HSP); Human diseases.; UPR; mTOR.

Figure 1

Overview of the different forms of autophagy in mammals. Macroautophagy, microautophagy and chaperone-mediated autophagy are three types of autophagy in mammals. Here, the main steps in these processes as well as the most important characteristic structures and the related mediators are presented.

Figure 2

Overview of the main steps in autophagy and the main genes involved.

Figure 3

The autophagic flux and generally used inhibitors. Inside the square, the autophagic flux is depicted. This is a dynamic process that can be modulated by the indicated drugs (grey text boxes) by affecting autophagosome induction and expansion (ON-rate) or by affecting autophagosome fusion or degradation (OFF-rate).

Figure 4

Regulation of the two mTOR complexes. mTORC1 is able to sense the amino acid concentration and energy state directly, but needs the PI3K-AKT axis to sense growth factor status. The downstream effects of mTORC1 are mainly mediated by 4E-BP1 and S6K1, which can be inhibited by the rapamycin-FKBP12 complex. mTORC2, as a brake-like inhibitor, decreases the extent of AKT-induced mTORC1 activation.

Figure 5

The different branches of the Unfolded Protein Response (UPR) and autophagy. The UPR is mediated by the ATF6, PERK, and IRE1 pathways. 1) After cleavage, ATF6 is able to up-regulate the expression of chaperones. 2) PERK is responsible for eIF2α activation. Activated, phosphorylated eIF2α-p then inhibits translation initiation, meanwhile stimulates ATF4 to transcriptionally activate CHOP and Atg12. In addition, ATF4 also activates GADD34 to decrease the activity of eIF2α-p, which forms a feedback loop. 3) IRE1 cleaves XBP1 to increase the expression of chaperones as well as speed up ERAD.

Figure 6

Protein homeostasis is mainly maintained by HSF1 and FOXO, two downstream targets of the insulin pathway. The formation of biochemistry-detectable aggregates is a dynamic process, which is initiated by accumulation of unfolded/misfolded proteins (Phase I), facilitated by the formation of intermediates (Phase II) leading to the appearance of detectable aggregates (Phase III). This process can be intervened by different cellular strategies, including HSPs mediated folding/refolding, as well as proteasome- and autophagy-mediated degradation. HSPs, up-regulated by HSF1 and FOXO, are mainly responsible for Phase I, in which the misfolded proteins can be either refolded to become functional normal proteins or degraded if refolding is unsuccessful. Once the intermediates are formed, autophagy starts playing a more important role. At the beginning of Phase II, the intermediates can still be handled by either HSPs or proteasome, and this response supposedly requires FOXO. At both Phase II and III, FOXO is also involved the induction of autophagy to clear large(r) protein aggregates.