Nucleophagy: from homeostasis to disease

Abstract

Nuclear abnormalities are prominent in degenerative disease and progeria syndromes. Selective autophagy of organelles is instrumental in maintaining cell homeostasis and prevention of premature ageing. Although the nucleus is the control centre of the cell by safeguarding our genetic material and controlling gene expression, little is known in relation to nuclear autophagy. Here we present recent discoveries in nuclear recycling, namely nucleophagy in physiology in yeast and nucleophagic events that occur in pathological conditions in mammals. The selective nature of degrading nuclear envelope components, DNA, RNA and nucleoli is highlighted. Potential effects of perturbed nucleophagy in senescence and longevity are examined. Moreover, the open questions that remain to be explored are discussed concerning the conditions, receptors and substrates in homeostatic nucleophagy.

Fig. 1

Types of autophagy. Macroautophagy involves the formation of the autophagosome. Initiation occurs with Unc-51-like kinase 1 activation and concomitant triggering of the phosphatidyl-inositol-3-kinase complex, Vps15/Vps34/Beclin 1 complex. In turn, two ubiquitin conjugation systems, ATG5/ATG7/ATG12 and LC3, are required for autophagosome formation and maturation. Autophagosome–lysosome fusion allows for degradation of autophagic substrates, such as p62. Microautophagy happens with direct interaction of the substrate and the lysosome. Chaperone-mediated autophagy requires chaperone targeting of specific proteins with the pentapeptide motif KFERQ to the lysosome-associated membrane protein LAMP-2A

Fig. 2

Piecemeal nucleophagy in yeast. Micronucleophagy occurs both under nutrient-rich conditions as well as nitrogen deprivation. The nucleus (purple) and the lytic vacuole (green) directly interact via tight junctions (blue) (a). In turn, nuclear ER bulges form b containing nucleophagic substrates such as the granular nucleolus (red), which are then pinched off (c). Finally, the nuclear derived vesicles are degraded in the lytic vacuole (d)

Fig. 3

Macronucleophagy in disease. Multiple autophagy substrates have been identified in pathological settings. In cancer, lamin A and B (grey) as well as nucleolar components (purple) have been identified while DNA (black) when not degraded properly could cause oncogenic stress. Neurodegeneration can occur as a result of lack of functional nuclear protein clearance, nucleophagy, of PolyQ aggregates (red) or of nuclear autophagy receptor p62

Fig. 4

Schematic diagram of potential model of nucleophagy under homeostasis. Under nutrient/oncogenic stress, different protein, ribosomal, rRNA and DNA constituents of the nucleus are degraded via macronucleophagy with direct interaction with nuclear LC3, interaction with the autophagic receptor p62 or a specific nucleophagic receptor located at the nuclear membrane to be transported to the autophagosome. Ultimately, nucleophagic substrates are delivered into the lysosome for degradation