Nucleus-Vacuole Junctions and Piecemeal Microautophagy of the Nucleus in<i>S. cerevisiae</i>

Kvam, Erik; Goldfarb, David S.

doi:10.4161/auto.3586

Cited by 107 publications

(120 citation statements)

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“…NVJs are involved in various cellular functions including mediating PMN, a distinct form of nuclear microautophagy in budding yeast (5). Upon nutrient depletion or rapamycin treatment NVJs proliferate and subsequently undergo engulfment into the lumen of the vacuole, leading to the eventual degradation of the engulfed nuclear membranes (6).…”

Section: Resultsmentioning

confidence: 99%

“…PMN is a selective autophagic recycling process stimulated by carbon or nitrogen starvation through the target of rapamycin signaling pathway in Saccharomyces cerevisiae. Upon nutrient starvation, the region of the nucleus in the vicinity of NVJs invaginates into the vacuolar lumen and forms a bleb-like structure, which is released as a vesicle and eventually degraded by vacuolar hydrolases (5,6). Because PMN occurs at the NVJ sites, their formation is essential for the initiation of the PMN process (7).…”

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confidence: 99%

“…MCSs are physically formed through dynamic and direct interactions between proteins that are located in two distinct subcompartments. The nucleus-vacuole junction (NVJ), one of the best-characterized MCSs, is a physical contact site between perinuclear and vacuolar membranes and mediates essential cellular processes such as piecemeal microautophagy of the nucleus (PMN) and lipid biosynthesis in yeast (4,5). PMN is a selective autophagic recycling process stimulated by carbon or nitrogen starvation through the target of rapamycin signaling pathway in Saccharomyces cerevisiae.…”

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confidence: 99%

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Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Jeong

Park

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Formation of the nucleus-vacuole junction (NVJ) is mediated by direct interaction between the vacuolar protein Vac8p and the outer nuclear endoplasmic reticulum membrane protein Nvj1p. Herein we report the crystal structure of Vac8p bound to Nvj1p at 2.4-Å resolution. Vac8p comprises a flexibly connected N-terminal H1 helix followed by 12 armadillo repeats (ARMs) that form a right-handed superhelical structure. The extended 80-Å-long loop of Nvj1p specifically binds the highly conserved inner groove formed from ARM1−12 of Vac8p. Disruption of the Nvj1p-Vac8p interaction results in the loss of tight NVJs, which impairs piecemeal microautophagy of the nucleus in Saccharomyces cerevisiae. Vac8p cationic triad (Arg276, Arg317, and Arg359) motifs interacting with Nvj1p are also critical to the recognition of Atg13p, a key component of the cytoplasm-to-vacuole targeting (CVT) pathway, indicating competitive binding to Vac8p. Indeed, mutation of the cationic triad abolishes CVT of Ape1p in vivo. Combined with biochemical data, the crystal structure reveals a Vac8p homodimer formed from ARM1, and this self-association, likely regulated by the flexible H1 helix and the C terminus of Nvj1p, is critical for Vac8p cellular functions. M embrane contact sites (MCSs) between subcellular compartments play pivotal roles in cellular processes such as cooperative lipid biosynthesis, ion homeostasis, and interorganellar trafficking of molecules in eukaryotic cells (1-3). MCSs are physically formed through dynamic and direct interactions between proteins that are located in two distinct subcompartments. The nucleus-vacuole junction (NVJ), one of the best-characterized MCSs, is a physical contact site between perinuclear and vacuolar membranes and mediates essential cellular processes such as piecemeal microautophagy of the nucleus (PMN) and lipid biosynthesis in yeast (4, 5). PMN is a selective autophagic recycling process stimulated by carbon or nitrogen starvation through the target of rapamycin signaling pathway in Saccharomyces cerevisiae. Upon nutrient starvation, the region of the nucleus in the vicinity of NVJs invaginates into the vacuolar lumen and forms a bleb-like structure, which is released as a vesicle and eventually degraded by vacuolar hydrolases (5, 6). Because PMN occurs at the NVJ sites, their formation is essential for the initiation of the PMN process (7). NVJs are also involved in lipid metabolism by recruiting the two lipid-modifying enzymes, oxystereol-binding proteins homology (Osh1p) involved in nonvesicular lipid trafficking and the enoyl-CoA reductase Tsc13p that mediates the synthesis of verylong-chain fatty acids (8-11).Previous studies revealed that NVJs are generated by forming tight interactions between Vac8p, a vacuolar membrane protein, and Nvj1p, a nuclear membrane protein (12). Vac8p was initially found as a key player in vacuole inheritance by cooperating with Vac17p, actin, profilin, and Myo2p (13). In addition, Vac8p has a crucial role in mediating the processing of aminopeptidase I through in...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Mechanistic insight into the nucleus–vacuole junction based on the Vac8p–Nvj1p crystal structure

Jeong

Park

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…9 -11). A second form of selective autophagy is piecemeal microautophagy of the nucleus, a process in which parts of the nucleus are engulfed and digested by the vacuole (12). Ribophagy, or selective autophagy of ribosomes, has also been documented (13), and ER-phagy has been suggested to occur in cells that are aggressively inducing the unfolded protein response (14,15).…”

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Aup1-mediated Regulation of Rtg3 during Mitophagy

Journo

Mor

Abeliovich

2009

Journal of Biological Chemistry

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Mitophagy is an autophagic process that degrades mitochondria by an intracellular engulfment that leads to their delivery into the lumen of the cell's hydrolytic compartment, such as the lysosome in animal cells or the vacuole in yeast. It is hypothesized that such processes serve a quality control function to prevent or slow the accumulation of malfunctioning mitochondria, which are thought in turn to underlie central aspects of the aging process in eukaryotic organisms. We recently identified a conserved mitochondrial protein phosphatase homolog, Aup1, which is required for efficient stationary phase mitophagy in yeast. In the present report, we demonstrate that the retrograde signaling pathway (RTG) is defective in aup1⌬ mutants. In agreement with a role for Aup1 in the regulation of the RTG pathway, we find that deletion of RTG3, a transcription factor that mediates the RTG response, causes a defect in stationary phase mitophagy and that deletion of AUP1 leads to changes in Rtg3 phosphorylation patterns under these conditions. In addition, we find that mitophagic conditions lead to induction of RTG pathway target genes in an Aup1-dependent fashion. Thus, our results suggest that the function of Aup1 in mitophagy could be explained through its regulation of Rtg3-dependent transcription.Mitochondria play an essential role in the physiology of eukaryotic cells. They are the sites of aerobic energy production and biosynthesis of amino acid precursors as well as nucleotide and lipid production. At the same time, mitochondria also present a threat to the cell, through production of reactive oxygen species and through the potential leakage of toxic factors, such as cytochrome c.It is generally hypothesized that quality control mechanisms scavenge malfunctioning mitochondrial compartments, safely neutralizing them before they damage cellular physiology (1, 2). One such quality control mechanism is autophagy, a catabolic process used by cells to transport cytoplasmic material for degradation in the lysosome (in animal cells) or the vacuole (in yeast, filamentous fungi, and plants) (3)(4)(5). Autophagic pathways can be classified either according to their molecular mechanism or according to their specificity. Thus, macroautophagy, the most well studied form of autophagy, is thought to be a relatively nonspecific scavenging mechanism that is induced in response to starvation cues (6 -8). Mechanistically, macroautophagy involves the generation of a cytosolic intermediate, an autophagosome, that consequently fuses with the lytic compartment or with elements of the endomembrane system that flow into the lytic compartment. On the other hand, microautophagy is a form of autophagy that involves direct involution of the vacuolar membrane, thus allowing import of material into the vacuolar lumen for degradation. There are several well documented types of selective autophagy. When Pichia pastoris is grown on methanol as a carbon source, it massively induces peroxisomes. When these cells are shifted to a better carbon source, su...

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“…Recently, hints for a unique microautophagic process termed piecemeal microautophagy of the nucleus (PMN), or micronucleophagy, in the yeast S. cerevisiae emerged. [8][9][10] PMN occurs at nucleus-vacuole (NV) junctions formed by interactions between Vac8 at the vacuolar membrane and Nvj1 in the nuclear envelope (nuclear ER) ( Fig. 1 stage I).…”

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confidence: 99%