Structure and function of ER membrane contact sites with other organelles

Phillips, Melissa J.; Voeltz, Gia K.

doi:10.1038/nrm.2015.8

Cited by 806 publications

(731 citation statements)

References 117 publications

(166 reference statements)

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“…We discovered that the mitochondrion was only distributed along the ventral surface, even during branching at mitosis. Further work will be required to understand how this positioning is achieved and whether there are distinct connections to the cytoskeleton to support this (Knoblach and Rachubinski, 2015a;Phillips and Voeltz, 2016). Even though the vast majority of the mitochondrion segregated to the two daughters through stages 6-8, we discovered that the mitochondrion was still connected across the cytoplasmic bridge between the two daughter cells in stage 8, with mitochondrial fission preceding cell abscission.…”

Section: Discussionmentioning

confidence: 86%

Patterns of organelle ontogeny through a cell cycle revealed by whole-cell reconstructions using 3D electron microscopy

Hughes¹,

Borrett²,

Towers³

et al. 2017

Development

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The major mammalian bloodstream form of the African sleeping sickness parasite Trypanosoma brucei multiplies rapidly, and it is important to understand how these cells divide. Organelle inheritance involves complex spatiotemporal re-arrangements to ensure correct distribution to daughter cells. Here, serial block face scanning electron microscopy (SBF-SEM) was used to reconstruct whole individual cells at different stages of the cell cycle to give an unprecedented temporal, spatial and quantitative view of organelle division, inheritance and abscission in a eukaryotic cell. Extensive mitochondrial branching occurred only along the ventral surface of the parasite, but the mitochondria returned to a tubular form during cytokinesis. Fission of the mitochondrion occurred within the cytoplasmic bridge during the final stage of cell division, correlating with cell abscission. The nuclei were located underneath each flagellum at mitosis and the mitotic spindle was located along the ventral surface, further demonstrating the asymmetric arrangement of cell cleavage in trypanosomes. Finally, measurements demonstrated that multiple Golgi bodies were accurately positioned along the flagellum attachment zone, suggesting a mechanism for determining the location of Golgi bodies along each flagellum during the cell cycle.

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Section: Discussionmentioning

confidence: 86%

Patterns of organelle ontogeny through a cell cycle revealed by whole-cell reconstructions using 3D electron microscopy

Hughes¹,

Borrett²,

Towers³

et al. 2017

Development

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“…The microtubules are of vital importance in this network and are in contact with the sarcoplasmic/ER and mitochondria (FIG. 2b); loss of contact results in Ca 2+ overload in the organelles, unfolded protein response in the ER, and mitochondrial dysfunction [50][51][52][53] . Contact between organelles and traf ficking through the cells is mediated by acetylated microtubules 52 .…”

Section: Key Pointsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…nucleus-vacuole junction | Vac8p | Nvj1p | membrane contact sites | crystal structure 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)(2)(3). MCSs are physically formed through dynamic and direct interactions between proteins that are located in two distinct subcompartments.…”

mentioning

confidence: 99%

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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Structure and function of ER membrane contact sites with other organelles

Cited by 806 publications

References 117 publications

Patterns of organelle ontogeny through a cell cycle revealed by whole-cell reconstructions using 3D electron microscopy

Patterns of organelle ontogeny through a cell cycle revealed by whole-cell reconstructions using 3D electron microscopy

Proteostasis in cardiac health and disease

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

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