Mammalian Homolog of<i>Drosophila retinal degeneration B</i>Rescues the Mutant Fly Phenotype

Chang, Jinghua Tsai; Milligan, Scott; Li, Yuanyuan; Chew, Christina E.; Wiggs, Janey L.; Copeland, Neal G.; Jenkins, Nancy A.; Campochiaro, Peter A.; Hyde, David R.; Zack, Donald J.

doi:10.1523/jneurosci.17-15-05881.1997

Cited by 58 publications

(69 citation statements)

References 47 publications

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“…Although Nir2 and rdgB are functionally interchangeable in Drosophila photoreceptor cells (Chang et al, 1997), the inconsistency with our results could be cell type specific. Early localization studies of rdgB in photoreceptor cells suggest that it is localized to the subrhabdomeric cisternal (SRC) membranes adjacent to the rhabdomeres (Vihtelic et al, 1993;Suzuki and Hirosawa, 1994).…”

Section: Vap-dependent Lipid Transfer Regulates Golgi Functioncontrasting

confidence: 94%

Coordinated Lipid Transfer between the Endoplasmic Reticulum and the Golgi Complex Requires the VAP Proteins and Is Essential for Golgi-mediated Transport

Peretti

Dahan

Shimoni

et al. 2008

MBoC

290

272

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Lipid transport between intracellular organelles is mediated by vesicular and nonvesicular transport mechanisms and is critical for maintaining the identities of different cellular membranes. Nonvesicular lipid transport between the endoplasmic reticulum (ER) and the Golgi complex has been proposed to affect the lipid composition of the Golgi membranes. Here, we show that the integral ER-membrane proteins VAP-A and VAP-B affect the structural and functional integrity of the Golgi complex. Depletion of VAPs by RNA interference reduces the levels of phosphatidylinositol-4-phosphate (PI4P), diacylglycerol, and sphingomyelin in the Golgi membranes, and it leads to substantial inhibition of Golgimediated transport events. These effects are coordinately mediated by the lipid-transfer/binding proteins Nir2, oxysterolbinding protein (OSBP), and ceramide-transfer protein (CERT), which interact with VAPs via their FFAT motif. The effect of VAPs on PI4P levels is mediated by the phosphatidylinositol/phosphatidylcholine transfer protein Nir2, which is required for Golgi targeting of OSBP and CERT and the subsequent production of diacylglycerol and sphingomyelin. We propose that Nir2, OSBP, and CERT function coordinately at the ER-Golgi membrane contact sites, thereby affecting the lipid composition of the Golgi membranes and consequently their structural and functional identities. INTRODUCTIONThe unique lipid compositions of the secretory and endocytic organelles are critical for maintaining their distinct structural and functional identities (van Meer, 2000). Their identities are maintained despite extensive interconnecting vesicular-trafficking pathways, and they require tight regulation of lipid sorting, metabolism, and transport (van Meer, 1993;Pomorski et al., 2001;van Meer and Sprong, 2004). Increasing lines of evidence suggest that lipid-transfer proteins (LTPs) play a major role in regulating the lipid composition of membranous organelles (Sprong et al., 2001;De Matteis et al., 2007). These proteins facilitate lipid transfer between a donor and acceptor membrane (Holthuis and Levine, 2005), and they usually contain dual-targeting determinants for different membrane compartments. LTPs have been proposed to efficiently transfer lipids at membrane contact sites (MCSs) (Holthuis and Levine, 2005;Levine and Loewen, 2006).MCSs or zones of close apposition between the ER membranes and other cellular membranes, including the plasma membrane (PM), the membranes of the vacuoles, mitochondria, peroxisomes, lipid droplets, late endosomes, lysosomes, and the Golgi apparatus, have been identified in all eukaryotes by morphological and biochemical studies (Shore and Tata, 1977;Levine, 2004;Levine and Loewen, 2006). More recently, electron tomography studies have identified close contacts (10 -20 nm) between the ER and the outer mitochondrial membrane (Perkins et al., 1997) and between a specialized trans-ER and the three trans-most cisternae of the Golgi complex (Ladinsky et al., 1999;Marsh et al., 2001Marsh et al., , 2004. This ...

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Section: Vap-dependent Lipid Transfer Regulates Golgi Functioncontrasting

confidence: 94%

Coordinated Lipid Transfer between the Endoplasmic Reticulum and the Golgi Complex Requires the VAP Proteins and Is Essential for Golgi-mediated Transport

Peretti

Dahan

Shimoni

et al. 2008

MBoC

290

272

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“…Typically, rdgB mutant flies begin to exhibit the mor- (32). In the last few years, four different mammalian genes encoding RdgB homologues have been cloned (1,10,26,29). Nir2 (also known as mRdgB) shares high sequence homology with the other family members, particularly within the N-terminal PI transfer domain and the C-terminal region (26).…”

Section: Discussionmentioning

confidence: 99%

“…Nirs belong to a growing family of highly conserved proteins that share structural features. Genes encoding Nirrelated proteins have been recently identified in worms, mammals, flies, and fish (1,10,12,26,29,46). They possess several putative functional domains, including an N-terminal phosphatidylinositol (PI) transfer domain that specifically transfers PI and phosphatidylcholine (32), an acidic region that binds calcium, six hydrophobic stretches, and a C-terminal PYK2-binding domain (26).…”

mentioning

confidence: 99%

“…They possess several putative functional domains, including an N-terminal phosphatidylinositol (PI) transfer domain that specifically transfers PI and phosphatidylcholine (32), an acidic region that binds calcium, six hydrophobic stretches, and a C-terminal PYK2-binding domain (26). Although the Nir family members are highly expressed in the retina and may be involved in inherited human retinal degeneration diseases (1,10,26), their cellular functions, as well as those of their Drosophila melanogaster homologue RdgB, remain largely unknown.…”

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confidence: 99%

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Nir2, a Novel Regulator of Cell Morphogenesis

Tian

Litvak

Toledo-Rodriguez

et al. 2002

Molecular and Cellular Biology

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Cell morphogenesis requires dynamic reorganization of the actin cytoskeleton, a process that is tightly regulated by the Rho family of small GTPases. These GTPases act as molecular switches by shuttling between their inactive GDP-bound and active GTP-bound forms. Here we show that Nir2, a novel protein related to Drosophila retinal degeneration B (RdgB), markedly affects cell morphology through a novel Rho-inhibitory domain (Rid) which resides in its N-terminal region. Rid exhibits sequence homology with the Rho-binding site of formin-homology (FH) proteins and leads to an apparent loss of F-actin staining when ectopically expressed in mammalian cells. We also show that Rid inhibits Rho-mediated stress fiber formation and lysophosphatidic acid-induced RhoA activation. Biochemical studies demonstrated that Nir2, via Rid, preferentially binds to the inactive GDP-bound form of the small GTPase Rho. Microinjection of antibodies against Nir2 into neuronal cells markedly attenuates neurite extension, whereas overexpression of Nir2 in these cells attenuates Rhomediated neurite retraction. These results implicate Nir2 as a novel regulator of the small GTPase Rho in actin cytoskeleton reorganization and cell morphogenesis.Cell morphogenesis is highly dependent on fine coordination among membrane biosynthesis, intracellular transport, and cytoskeletal organization (4, 50). Small GTPases of the Rho family are essential mediators of a variety of morphogenetic events required for normal development of multicellular organisms (39). Their role in cell morphogenesis is strongly related to their ability to reorganize the actin cytoskeleton (16). The members of this family of proteins, which includes Rho, Rac, and Cdc42, elicit their cellular function by shuttling between their inactive GDP-bound and their active GTP-bound forms (42, 45). The activation state of Rho, like that of the other family members, is tightly regulated by numerous intracellular proteins that can be functionally divided into three groups: the GDIs (GDP-dissociation inhibitors), the GAPs (GTPase-activating proteins), and the GEFs (GDP/GTP exchange factors). These upstream regulators negatively or positively regulate Rho activity, while Rho downstream effectors mediate Rho signaling to elicit Rho-regulated cellular functions (6, 7). Over the last few years, several Rho effector proteins have been identified (5). Among them, PKN, rhophilin, and rhotekin possess a conserved Rho-binding motif (35), while a second Rho-binding motif has been recently identified in ROCK-I and ROK␣ (15). A Rho-binding site has also been mapped to the N-terminal portion of three formin-homology (FH) proteins. Although no consensus Rho-binding site has been identified among these family members, their N-terminal portion contains a conserved motif that falls within the Rhointeraction domain defined elsewhere for Bnr1p and mDia1 (47).We recently isolated a novel family of human genes designated Nirs (Nir1, Nir2, and Nir3), which are the mammalian homologues of the Drosophila retinal deg...

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“…The presence or absence of the 2.7-kb TaqI M. spretus-specific fragment was followed in the backcrossed mice. A description of the probes and RFLPs for the loci linked to Tem1/endosialin including Gal, Adrbk1, and Cd5 has been reported previously (26). Recombination distances were calculated using Map Manager, version 2.6.5.…”

Section: Methodsmentioning

confidence: 99%

Molecular Characterization of the MouseTem1/endosialin Gene Regulated by Cell Density in Vitro and Expressed in Normal Tissues in Vivo

Opavský¹,

Haviernik²,

Jurkovičová³

et al. 2001

Journal of Biological Chemistry

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Human tumor endothelial marker 1/endosialin (TEM1/ endosialin) was recently identified as a novel tumor endothelial cell surface marker potentially involved in angiogenesis, although no specific function for this novel gene has been assigned so far. It was reported to be expressed in tumor endothelium but not in normal endothelium with the exception of perhaps the corpus luteum. Here we describe the cDNA and genomic sequences for the mouse Tem1/endosialin homolog, the identification and characterization of its promoter region, and an extensive characterization of its expression pattern in murine and human tissues and murine cell lines in vitro. The single copy gene that was mapped to chromosome 19 is intronless and encodes a 92-kDa protein that has 77.5% overall homology to the human protein. The remarkable findings are 1) this gene is ubiquitously expressed in normal human and mouse somatic tissues and during development, and 2) its expression at the mRNA level is density-dependent and up-regulated in serum-starved cells. In vitro, its expression is limited to cells of embryonic, endothelial, and preadipocyte origin, suggesting that the wide distribution of its expression in vivo is due to the presence of vascular endothelial cells in all the tissues. The ubiquitous expression in vivo is in contrast to previously reported expression limited to corpus luteum and highly angiogenic tissues such as tumors and wound tissue.

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Mammalian Homolog ofDrosophila retinal degeneration BRescues the Mutant Fly Phenotype

Cited by 58 publications

References 47 publications

Coordinated Lipid Transfer between the Endoplasmic Reticulum and the Golgi Complex Requires the VAP Proteins and Is Essential for Golgi-mediated Transport

Coordinated Lipid Transfer between the Endoplasmic Reticulum and the Golgi Complex Requires the VAP Proteins and Is Essential for Golgi-mediated Transport

Nir2, a Novel Regulator of Cell Morphogenesis

Molecular Characterization of the MouseTem1/endosialin Gene Regulated by Cell Density in Vitro and Expressed in Normal Tissues in Vivo

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