Functional Mutation Analysis Provides Evidence for a Role of REEP1 in Lipid Droplet Biology

Falk, Julia; Rohde, Magdalena; Bekhite, Mohamed M.; Neugebauer, Sophie; Hemmerich, Peter; Kiehntopf, Michael; Deufel, Thomas; Hübner, Christian A.; Beetz, Christian

doi:10.1002/humu.22521

Cited by 58 publications

(46 citation statements)

References 32 publications

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“…Interestingly, mutations related to disease have been mapped to the homologous region of REEP1, including P19R, P19L, A20E, and S23F (40-42), all of which exhibit localization defects (42,43). These REEP1 positions are conserved in Yop1p and lie within the C-terminal half of TM2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, the hydrophobicity of the amino acids in positions 110-114 (sequence ILYLI), combined with the observation that helical kinks rather than breaks are often introduced in the helical turn preceding Pro (29), suggests that these residues are more likely an extension of TM4. Furthermore, sequence conservation and HSP-associated genetic mutants more strongly implicate the residues around S107 and K108 for a structural or functional role: Position K108 is highly conserved as a charged residue with a preference for Asp, while mutations at the positions homologous to S107 and K108 in REEP1 are known to cause HSP (41,46), although the molecular basis remains unknown (42). Thus, we postulate that the TM3/ TM4 helical turn occurs near W106/S107/K108, and that Yop1p therefore contains four hydrophobic helices long enough to span the ER bilayer fully (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Brady

Claridge

Smith

et al. 2015

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

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The integral membrane proteins of the DP1 (deleted in polyposis) and reticulon families are responsible for maintaining the high membrane curvature required for both smooth endoplasmic reticulum (ER) tubules and the edges of ER sheets, and mutations in these proteins lead to motor neuron diseases, such as hereditary spastic paraplegia. Reticulon/DP1 proteins contain reticulon homology domains (RHDs) that have unusually long hydrophobic segments and are proposed to adopt intramembrane helical hairpins that stabilize membrane curvature. We have characterized the secondary structure and dynamics of the DP1 family protein produced from the YOP1 gene (Yop1p) and identified a C-terminal conserved amphipathic helix (APH) that, on its own, interacts strongly with negatively charged membranes and is necessary for membrane tubule formation. Analyses of DP1 and reticulon family members indicate that most, if not all, contain C-terminal sequences capable of forming APHs. Together, these results indicate that APHs play a previously unrecognized role in RHD membrane curvature stabilization.T he endoplasmic reticulum (ER) is the largest membranebound organelle in the eukaryotic cell and adopts diverse morphologies, including tubules that extend outward to the cell periphery and sheet-like structures closer to the nucleus (1, 2). The regions of high membrane curvature that are found in the ER tubules and sheets are stabilized by the DP1 (deleted in polyposis) and reticulon classes of integral membrane proteins (3-5). Consistent with their role in ER morphology, similar proteins have not been found in prokaryotes (6).There are six human DP1 proteins originally identified as accessory proteins facilitating the expression of odorant receptors, and thus termed receptor expression-enhancing proteins (REEPs) (7). The ability of REEPs to facilitate receptor trafficking has recently been related back to their ER shaping activities (8). The importance of REEPs in ER morphology is also highlighted by their implication in human diseases that are associated with neurons having long axons and requiring an extended tubular ER (9, 10). For example, mutations in the transmembrane domain of REEP1, which is primarily expressed in neurons (11), lead to pure forms of hereditary spastic paraplegia (HSP) (12, 13).The reticulon family in humans comprises four members, Rtn1-Rtn4 (6). Rtn4 is of particular interest because it is primarily responsible for generating or stabilizing the tubular ER in mammalian cells. Rtn4 is critical in neuronal cell processes because it inhibits spontaneous neurite outgrowth (14) and restricts neuronal plasticity (15), and it has been implicated in several neural diseases, including schizophrenia and motor neuron disease (16-18).The DP1 and reticulon proteins have in common a region containing two, unusually long hydrophobic segments (≈35 aa in length each) known as a reticulon homology domain (RHD) (6). In humans, REEPs 1-6 are similar overall; however, the RHD of REEPs 1-4 is truncated (Fig. S1). REEPs 1-4 also possess...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Brady

Claridge

Smith

et al. 2015

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

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“…Atlastin mediates fusion of ER tubules and also controls the size of lipid droplets [85]. REEP1 maintains the high curvature of ER tubules, and when overexpressed together with Atlastin increases lipid-droplet size [85, 86]. Seipin, an integral membrane protein at the ER-droplet junction, is important for lipid droplet formation and maintenance [87, 88].…”

Section: Lipid Droplets and The Nervous Systemmentioning

confidence: 99%

Expanding Roles for Lipid Droplets

2015

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Summary Lipid droplets are the intracellular sites for neutral lipid storage. They are critical for lipid metabolism and energy homeostasis, and their dysfunction has been linked to many diseases. Accumulating evidence suggests that the roles lipid droplets play in biology are significantly broader than previously anticipated. Lipid droplets are the source of molecules important in the nucleus: they can sequester transcription factors and chromatin components and generate the lipid ligands for certain nuclear receptors. Lipid droplets have also emerged as important nodes for fatty acid trafficking, both inside the cell and between cells. In immunity, new roles for droplets, not directly linked to lipid metabolism, have been uncovered, as assembly platforms for specific viruses and as reservoirs for proteins that fight intracellular pathogens. Until recently, knowledge about droplets in the nervous system has been minimal, but now there are multiple links between lipid droplets and neurodegeneration: Many candidate genes for Hereditary Spastic Paraplegia also have central roles in lipid-droplet formation and maintenance, and mitochondrial dysfunction in neurons can lead to transient accumulating of lipid droplets in neighboring glial cells, an event that may, in turn, contribute to neuronal damage. As the cell biology and biochemistry of lipid droplets are increasingly well understood, the next few years should yield many new mechanistic insights into these novel functions of lipid droplets.

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“…LD-associated proteins are abundantly expressed in the brain and neurons and are especially susceptible to oxidative stress induced by lipid peroxidation [100]. In recent years, several ER-resident proteins mutated in HSPs were found to be involved in the regulation of LD size and formation [101][102][103]. For instance, depletion of atlastin-1 or expression of a dominant-negative mutant resulted in LD size reduction, whereas atlastin-1 overexpression had the opposite effect [101].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

102

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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Functional Mutation Analysis Provides Evidence for a Role of REEP1 in Lipid Droplet Biology

Cited by 58 publications

References 32 publications

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Expanding Roles for Lipid Droplets

Carnitine palmitoyltransferase 1C: From cognition to cancer

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