Autophagy Signalling

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Autophagy Signalling

Hans‐Uwe Simon, University of Bern, Bern, Switzerland
Robert Friis, University of Bern, Bern, Switzerland

Published online: December 2016

DOI: 10.1002/9780470015902.a0026792

Full Article on Wiley Online Library

Abstract
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Abstract

Autophagy comprises several evolutionarily conserved mechanisms for transport and uptake of proteins and even cytoplasmic organelles into the lysosome. Macroautophagy sequesters cytoplasmic elements, sometimes with elegant selectivity and sometimes just in bulk, into double membrane vacuoles which are subsequently fused with lysosomes for degradation. In mammals, such recycling of protein aggregates and malfunctioning organelles allows macroautophagy to facilitate recovery of constituents for new protein synthesis or ATP (adenosine triphosphate) production, but provides also for selective removal of signalling proteins (e.g. signalphagy) and serves as an effective mechanism for quality control on whole organelles (e.g. mitophagy). Autophagy signalling includes both numerous options for its regulation by posttranslational modifications, for example phosphorylation/dephosphorylation and acetylation/deacetylation, as well as by transcriptional upregulation with many transcription factors. Autophagy shares functional components with other pathways and stands always balanced between different cell fates: quiescence, that is a temporary cell cycle arrest, senescence or cell death by apoptotic or nonapoptotic mechanisms.

Key Concepts

Basal autophagy is always present in most cell types, but can be intensified or diminished by posttranslational mechanisms affecting levels of ‘free’ autophagy‐related proteins and transcriptional regulation of their genes.
Autophagy is used as a process for compensation of nutritional imbalances and thus is responsible for adjustments to anabolic/catabolic metabolism as well as ox/redox balance and mitochondrial function.
Autophagic flux means that the receptor/adaptor proteins, for example p62/SQSTM1, which are responsible for bridging of polyubiquitinated cargo proteins or organelles to LC3, are thus themselves subject to continuous degradation.
A close integration with physiological needs regulates autophagy initiation and the expression of the required autophagy‐related and lysosomal proteins.
Autophagy is involved with the determination of cell fate, quiescence, senescence and/or cell death and can play a part in oncogenic cell selection and tumour progression.

Keywords: autophagy; ATG5; ATG7; Beclin 1; mTORC1; p38 MAPK; p53; Nrf2; p62/SQSTM1; TFEB

	Figure 1. Pathways regulating nutritional stress responses. Red arrows point out pathways which can be activated by the stress of inadequate nutritional resources, amino acids (AA), (Glucose), (O₂) or growth factor (GF) occupancy on the receptor (R). (P) indicates phosphorylations. Any deficiencies lead finally to the initiation of Autophagy (as indicated by green arrows) inhibitory pathways are shown in black. Under all stress conditions, AMPK (AMP‐dependent protein kinase) plays a central role because it can determine the specific phosphorylation/activation of TSC1/2 (P), thus regulating Rheb GTPase activity and, hence, its conversion to the inactive, GDP (guanosine diphosphate)‐bound form which elicits mTORC1 inactivation and displacement from the lysosomal Rag complex. Thereupon, the inhibitory block on autophagy imposed by mTORC1 is relieved, indicated by a black arrow crossed with (//). AMPK is able to detect a declining energy charge; this can be owing to insufficient glucose, O₂, or simply to mitochondrial inefficiency resulting in an increasing ROS (reactive oxygen species) concentration. ROS accumulation resulting from metabolic imbalance or mitochondrial damage allows oxidised (ox) ATM (ataxia telangiectasia mutated) dimers to phosphorylate and activate AMPK also with consequent TSC1/2 activation, Rheb GTPase activation and resulting mTORC1 inactivation. GF stimulation is essential for AKT to maintain TSC1/2 in an inactive state; however, AMPK can take on multiple distinct phosphorylations at different sites and is able to override the input on TSC1/2 contributed by AKT as shown by the (//) in this pathway. AMPK is even able to phosphorylate ULK1/2 directly, activating autophagy.
	Figure 2. The DNA (deoxyribonucleic acid) damage response after a DNA double strand break. Red arrows delineate the pathways which become activated in a DDR (DNA damage response), enforcing mTORC1 inactivation and initiation of Autophagy (green arrows). Activated monomer ATM at the site of DNA double strand breaks phosphorylates and activates Chk2, which is followed by p53 phosphorylation and activation. (P) indicates phosphorylations. Nuclear p53 transactivates p21^CDKN1A to induce growth arrest, proapoptotic proteins such as Puma, Noxa and Bax (potentially inducing Apoptosis), as well as proautophagic proteins such as sestrins. After DNA damage, activated p53 plays a complex role because it is translocated to the cytoplasm where it activates LKB1 to phosphorylate AMPK, thus providing a signal for TSC1/2 activation, converting Rheb to the GDP‐bound form, which leads to mTORC1 inactivation and displacement from the lysosomal Rag complex. Autophagy then initiates spontaneously following ULK1/2 autophosphorylation upon release from mTORC1 inhibition but also AMPK is also able to phosphorylate ULK1/2 directly, thus providing an immediate stimulation to autophagy (see green arrows). Under nutritional stress, signalling from AMPK in an upstream direction via LBK1 can also activate/phosphorylate p53 initiating a stress response (see yellow dotted arrows). Cytoplasmic p53 (cyto p53) is found normally in the cytoplasm. It inhibits autophagy ‘tonically’ by complexing with FIP200, but activated p53 in the DDR commits it to proteasomal degradation in a stress response. However, intensive stress can also provoke cytop53 translocation into mitochondria (Mito) followed by apoptosis (black arrows).
	Figure 3. The MiT/TFE transcription factor TFEB is activated and translocated into the nucleus for mitophagy. Mitophagy is a massive, selective autophagic degradation requiring increased resources in both autophagic and lysosomal proteins. Their expression depends on the MiT/TFE (microphtalmia/transcription factor E) transcription factor family, here typified by TFEB. TFEB is retained in the cytoplasm with the chaperone 14‐3‐3 after its phosphorylation by active mTORC1. (P) indicates phosphorylations. Following mitochondrial dysfunction, PINK1 kinase localises to the outer mitochondrial membrane where it phosphorylates mitochondrial surface proteins and recruits the E3 ubiquitin ligase, Parkin, phosphorylating Parkin and its ubiquitin. Unphosphorylated ubiquitin on parkin is indicated by a differing color. Phosphorylated ubiquitin serves as a trigger for the formation of an adjacent phagophore and stimulates its development. The receptor/adaptor NDP52 (52) binds phosphorylated ubiquitin at the mitochondrion, finally allowing sequestration into the phagophore by serving as a bridge to the LC3‐PE (LC3) on the phagophore. In parallel, TFEB activation and translocation into the nucleus allows transactivation of numerous lysosomal and autophagy genes.
	Figure 4. By regulating the selective autophagy of KEAP1, p62 assures its own transcription. Because SQSTM1, the gene for p62, is transcribed by Nrf2, a feed forward loop is established when ROS levels rise. Transcription factor Nrf2 is responsible for transcription of many antioxidant (Anti‐ox) genes, but is subject to proteasomal degradation if it undergoes ubiquitination by the ubiquitin ligase KEAP1. However, as the autophagic cargo receptor, p62 (62), has an affinity for and complexes with KEAP1, this complex, together with aggregates (Ag) of polyubiquitinated proteins, is bridged to LC3‐PE (LC3) at the developing phagophore and degraded, thus leaving Nrf2 available for nuclear translocation and transactivation of its targets, including especially p62.

Article Title:	Autophagy Signalling
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