Emerging Role of the Nucleolar Stress Response in Autophagy

Abstract

Autophagy represents a conserved self-digestion program, which allows regulated degradation of cellular material. Autophagy is activated by cellular stress, serum starvation and nutrient deprivation. Several autophagic pathways have been uncovered, which either non-selectively or selectively target the cellular cargo for lysosomal degradation. Autophagy engages the coordinated action of various key regulators involved in the steps of autophagosome formation, cargo targeting and lysosomal fusion. While non-selective (macro)autophagy is required for removal of bulk material or recycling of nutrients, selective autophagy mediates specific targeting of damaged organelles or protein aggregates. By proper action of the autophagic machinery, cellular homeostasis is maintained. In contrast, failure of this fundamental process is accompanied by severe pathophysiological conditions. Hallmarks of neuropathological disorders are for instance accumulated, mis-folded protein aggregates and damaged mitochondria. The nucleolus has been recognized as central hub in the cellular stress response. It represents a sub-nuclear organelle essential for ribosome biogenesis and also functions as stress sensor by mediating cell cycle arrest or apoptosis. Thus, proper nucleolar function is mandatory for cell growth and survival. Here, I highlight the emerging role of nucleolar factors in the regulation of autophagy. Moreover, I discuss the nucleolar stress response as a novel signaling pathway in the context of autophagy, health and disease.

Keywords: aggregates; autophagy; mitochondria; neuron; nucleolar stress; nucleoli; rRNA processing; ribosome biogenesis.

FIGURE 1

The classical p53-dependent nucleolar stress response pathway. Nucleolar stress is caused by e.g., mutation of ribosomal proteins (RP), impaired transcription of rDNA into rRNA, abrogated rRNA processing, disrupted nucleolar integrity as well as by genotoxic stressors, such as UV irradiation. As a consequence, RPs are released and bind and inhibit the E3-ubiquitin ligase MDM2. In turn, p53 is no longer degraded in the proteasome and is stabilized. Given the p53 accumulation, p53-mediated effects are propagated, such as cell cycle arrest, senescence, apoptosis or genotoxic stress. Note that also p53-independent routes exist, which are not indicated in this scheme.

FIGURE 2

Simplified model of cargo targeted by bulk autophagy or mitophagy. The phagophore forms around bulk material, such as proteins and organelles during bulk (macro)autophagy. The phagophore is a double-membranous structure, which forms around the cargo and gives rise to the autophagosome. In contrast, mitophagy reflects selective recruitment of ubiquitinated (yellow) mitochondria (red/orange) by the mitophagy receptors (blue) to LC3-II (green) located at the phagophore.

FIGURE 3

Removal of protein aggregates by selective autophagy. Aggregated proteins (red) are bound by the autophagy receptor p62 (blue), which itself has interaction domains for autophagosomal LC3 (green, lipidated LC3-II) and ubiquitin (yellow). The cargo is engulfed by the mature autophagosome and subsequently fuses with the lysosome to form the autolysosome, in which the cellular material is degraded by acidic hydrolases (orange).

FIGURE 4

A simplified model of mTOR signaling, and effect of nucleolar stress on p53. Growth factors, energy status, amino acid availability, oxygen levels and genotoxic stress can result in mTORC1 activation. p53 is stabilized either by genotoxic stress and/or nucleolar stress. p53 inhibits mTORC1 by activation of AMPK and TSC1/TSC2 (Tuberous sclerosis proteins 1 and 2). mTORC1 further activates autophagy by inhibitory effects on the ULK1 complex, composed of ULK1, ATG13 and FIP200. mTORC1 promotes protein synthesis by (i) S6K activation, which stimulates phosphorylation of S6 and thereby ribosome biogenesis, as well as by (ii) inhibitory effects on 4E-BP1 and eIF-4E. As a consequence, translation is activated. Furthermore, mTORC1 influences mitochondrial biogenesis and metabolism.

FIGURE 5

Model: Nucleolar stress in apoptosis, autophagy and disease. Nucleolar stress triggers either the classical p53 response or p53-independent mechanisms. In turn, transcriptional programs and/or transcription-independent mechanisms are induced, which finally cause mitochondrial changes, autophagy or apoptosis. As a consequence of nucleolar stress, not only apoptosis but also autophagy is emerging as a tightly coupled stress response pathway for the formation or cure of pathological conditions.