Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein

Henne, W. Mike; Zhu, Lu; Balogi, Zsolt; Stefan, Christopher J.; Pleiss, Jeffrey A.; Emr, Scott D.

doi:10.1083/jcb.201503088

Cited by 146 publications

(196 citation statements)

References 34 publications

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“…ER appositions were also found with lysosomes and multivesicular bodies (40,62,92), as expected. Such appositions were not systematically investigated, given the sparse presence of these organelles in the neuronal volumes that we have reconstructed.…”

Section: Discussionsupporting

confidence: 60%

Contacts between the endoplasmic reticulum and other membranes in neurons

Whiteus

et al. 2017

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

412

501

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Close appositions between the membrane of the endoplasmic reticulum (ER) and other intracellular membranes have important functions in cell physiology. These include lipid homeostasis, regulation of Ca 2+ dynamics, and control of organelle biogenesis and dynamics. Although these membrane contacts have previously been observed in neurons, their distribution and abundance have not been systematically analyzed. Here, we have used focused ion beam-scanning electron microscopy to generate 3D reconstructions of intracellular organelles and their membrane appositions involving the ER (distance ≤30 nm) in different neuronal compartments. ER-plasma membrane (PM) contacts were particularly abundant in cell bodies, with large, flat ER cisternae apposed to the PM, sometimes with a notably narrow lumen (thin ER). Smaller ER-PM contacts occurred throughout dendrites, axons, and in axon terminals. ER contacts with mitochondria were abundant in all compartments, with the ER often forming a network that embraced mitochondria. Small focal contacts were also observed with tubulovesicular structures, likely to be endosomes, and with sparse multivesicular bodies and lysosomes found in our reconstructions. Our study provides an anatomical reference for interpreting information about interorganelle communication in neurons emerging from functional and biochemical studies.FIB-SEM | thin ER | Stim1 | spine apparatus | subsurface cisternae

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Section: Discussionsupporting

confidence: 60%

Contacts between the endoplasmic reticulum and other membranes in neurons

Whiteus

et al. 2017

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

412

501

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“…Another, FATP5, has activation activity towards bile acids and is involved in secondary bile acid metabolism 92, 93 . Finally, there is evidence these proteins are localized to the endoplasmic reticulum in addition to the plasma membrane, which may occur at regions of juxtaposition between the two membranes ( e.g ., see 94, 95 ). None-the-less, both knockdown and over expression studies of several members of the FATP family are consistent with the conclusion they function in the process governing the transport exogenous fatty acids into the cell in a highly regulated manner.…”

Section: Fatp/scl27 Family Members As Drug Targetsmentioning

confidence: 97%

Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

et al. 2016

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Summary The fatty acid transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the transport of exogenous fatty acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated transport of fatty acids and thus represent a therapeutic target to delimit the acquisition of fatty acids that contribute to disease as in the case of fatty acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of fatty acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on transport directly. While several classes of compounds were identified as potential inhibitors of fatty acid transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating fatty acid transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in fatty acid transport. These studies identified two compounds, 5′-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3′-indoline]-2′-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective fatty acid transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.

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“…Ltc1p (also known as Lam6p), an ER integral membrane protein, is localized to NVJ via its binding to Vac8p (31,33). Another integral ER membrane protein, Mdm1p, binds vacuolar phosphatidylinositol-3-phosphate through its PX domain, forming NVJs (32). Although the molecular composition or architecture of NVJs formed by these proteins remains unknown, their contribution to the formation of a tight NVJ is likely to be limited because disruption of the Nvj1p-Vac8p interaction largely impaired the tight apposition between the nucleus and the vacuole (Fig.…”

Section: Discussionmentioning

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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Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein

Abstract: Mdm1 is a novel interorganelle tethering protein that localizes to yeast ER–vacuole/lysosome junctions, and Mdm1 truncations analogous to disease-associated Snx14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism.

Cited by 146 publications

References 34 publications

Contacts between the endoplasmic reticulum and other membranes in neurons

Contacts between the endoplasmic reticulum and other membranes in neurons

Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

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

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