ER homeostasis and autophagy

Abstract

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

Keywords: Autophagy; ER homeostasis; ER stress; ER-phagy; proteostasis; unfolded protein response.

Figure 1. Outcomes of ER stress

Perturbation of ER homeostasis or ‘ER stress’ (blue), is ameliorated by the triggering of signalling cascades (yellow), which in turn engage downstream effector mechanisms (green). Generally speaking, these mechanisms restore homeostasis. This review will discuss these pathways and mechanisms, with particular focus on autophagy as a potential effector and, in further detail, selective autophagic degradation of ER luminal contents or ER (ER-quality control (ERQC)-autophagy, ER-associated degradation (ERAD)-II and ER-phagy).

Figure 2. Engagement of autophagy by ER stress and molecular model for ER-phagy events

(1) Under normal ER homeostasis, the ER luminal chaperone protein BiP/GRP78 binds to the UPR sensor proteins PERK, IRE1α and ATF6. (2) Upon the presence of ER stress caused by unfolded protein (pink lightning), BiP/GRP78 dissociates from UPR sensors and binds to the unfolded protein, thus activating ER stress sensors. (3) PERK is able to up-regulate the transcription of numerous autophagy genes and cargo receptors through its effector transcription factors ATF4 and CHOP, resulting in an increase in general autophagic flux. (4) Any of the UPR sensors could hypothetically increase the transcription in ER-phagy receptor genes. In the case of CCPG1, this indeed occurs. (5) In the case of CCPG1 protein, an interaction with FIP200 is required for recruitment of ER into autophagosomes. It is unclear whether this happens at the ER surface (depicted) or at a latter stage of the pathway. FIP200 is rarely found on the inner surface of autophagosomes, arguing for the former. (6) The ER becomes scissioned. Concomitant with this, ER-phagy receptors bind to ATG8 proteins via their LIR motifs, linking fragmented ER to the isolation membrane. (7) The isolation membrane grows and encloses to form an autophagosome, which will eventually fuse with the lysosome and degrade the ER fragment. (8) It is hypothetically possible that ER stress directly engages and activates ER-phagy receptors independent of transcriptional induction and UPR sensors. To date, there are four described mammalian ER-phagy receptors (top panel). All receptors share the common characteristic of at least one cytosolic LIR motif (yellow star). CCPG1 possesses additional cytosolic FIP200-interacting region (FIR) motifs (red star).