TIP47 functions in the biogenesis of lipid droplets

Bulankina, Anna V.; Deggerich, Anke; Wenzel, Dirk; Mutenda, Kudzai E.; Wittmann, J.; Rudolph, M.G.; Burger, Koert N.J.; Höning, Stefan

doi:10.1083/jcb.200812042

Cited by 237 publications

(272 citation statements)

References 51 publications

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“…By demonstrating that the C-terminal region of ADPH folds independently of the N-terminal region and that it binds liposome membranes, we now have direct evidence that ADPH is composed of two independently functioning domains: an N-terminal domain that targets it to CLD and a C-terminal domain that mediates membrane binding. A similar functional organization of TIP47 has been proposed (39). Although direct evidence of the ability of the C-terminal region of TIP47 to bind membranes has not been demonstrated, it is likely that it also contains membrane binding elements based on the similarity to the ADPH C-terminal sequence and on observations that recombinant full-length TIP47 induces fragmentation of liposomes into discs (39).…”

Section: Discussionmentioning

confidence: 96%

“…A similar functional organization of TIP47 has been proposed (39). Although direct evidence of the ability of the C-terminal region of TIP47 to bind membranes has not been demonstrated, it is likely that it also contains membrane binding elements based on the similarity to the ADPH C-terminal sequence and on observations that recombinant full-length TIP47 induces fragmentation of liposomes into discs (39). The apparent similarities in the structural properties and functional organizations of ADPH and TIP47 raise questions about whether these proteins serve similar physiological roles.…”

Section: Discussionmentioning

confidence: 99%

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The Adipophilin C Terminus Is a Self-folding Membrane-binding Domain That Is Important for Milk Lipid Secretion

Chong

Russell

Schaack

et al. 2011

Journal of Biological Chemistry

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Cytoplasmic lipid droplets (CLD) in mammary epithelial cells undergo secretion by a unique membrane envelopment process to produce milk lipids. Adipophilin (ADPH/Plin2), a member of the perilipin/PAT family of lipid droplet-associated proteins, is hypothesized to mediate CLD secretion through interactions with apical plasma membrane elements. We found that the secretion of CLD coated by truncated ADPH lacking the C-terminal region encoding a putative four-helix bundle structure was impaired relative to that of CLD coated by full-length ADPH. We used homology modeling and analyses of the solution and membrane binding properties of purified recombinant ADPH C terminus to understand how this region possibly mediates CLD secretion. Homology modeling supports the concept that the ADPH C terminus forms a four-helix bundle motif and suggests that this structure can form stable membrane bilayer interactions. Circular dichroism and protease mapping studies confirmed that the ADPH C terminus is an independently folding ␣-helical structure that is relatively resistant to urea denaturation. Liposome binding studies showed that the purified C terminus binds to phospholipid membranes through electrostatic dependent interactions, and cell culture studies documented that it localizes to the plasma membrane. Collectively, these data provide direct evidence that the ADPH C terminus forms a stable membrane binding helical structure that is important for CLD secretion. We speculate that interactions between the four-helix bundle of ADPH and membrane phospholipids may be an initial step in milk lipid secretion.Milk lipids are an essential source of neonatal calories and provide nutrients in the form of fatty acids and bioactive lipids that are required for growth and development (1). Milk lipids are delivered to the newborn as milk fat globules (MFG) 4 derived from triglyceride-rich cytoplasmic lipid droplets (CLD) (2). Adipophilin (ADPH/ADRP/Adfp/Plin2), a member of the perilipin/PAT (perilipin/adipophilin/TIP47) family of proteins (3), is an abundant MFG protein (4 -6) and a prominent CLDassociated protein of mammary epithelial cells (7,8). PAT proteins have been shown to promote the formation and accumulation of CLD in a variety of tissues (9, 10) and are also implicated in the trafficking and secretion of CLD (2, 9). The lactating mammary gland is an ideal system to study the recurrent cycles of CLD formation, accumulation, and secretion, and previous work from our laboratory has implicated ADPH in each of these processes (5,8,11).CLD are secreted during lactation by an apocrine process where the apical plasma membrane engulfs associated CLD, which are then released by a budding process to form MFG (2). Two key regulators of CLD secretion are the transmembrane protein butyrophilin (BTN) and the cytoplasmic homodimer, xanthine oxidoreductase (XOR). Mice deficient in either of these proteins display impaired CLD envelopment and secretion (12, 13). In addition to being an abundant protein on mammary epithelial CLD and secreted MFG ...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

The Adipophilin C Terminus Is a Self-folding Membrane-binding Domain That Is Important for Milk Lipid Secretion

Chong

Russell

Schaack

et al. 2011

Journal of Biological Chemistry

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“…These screens have surprisingly revealed that more than 1% of the genes in eukaryotic genomes are involved in LD biology (3)(4)(5), underscoring the importance of the LD in normal cellular physiology. Several members of the perilipin family, namely plin2, plin3, and plin4, have been implicated as having roles in LD formation (6)(7)(8). However, most evidence supports a role of the plin family in the regulated lipolysis of LDs (9).…”

mentioning

confidence: 92%

Direct binding of triglyceride to fat storage-inducing transmembrane proteins 1 and 2 is important for lipid droplet formation

Gross

Zhan

Silver

2011

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

154

149

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The process of lipid droplet (LD) formation is an evolutionarily conserved process among all eukaryotes and plays an important role in both cellular physiology and disease. Recently, fat storageinducing transmembrane proteins 1 and 2 (FIT1/FITM1 and FIT2/ FITM2) were discovered as an evolutionarily conserved family of proteins involved in fat storage. In mammals, FIT1 is expressed primarily in skeletal muscle and FIT2 is expressed primarily in adipose, raising the possibility that FIT1 and FIT2 have unique functions. These proteins are exclusively localized to the endoplasmic reticulum (ER) and mediate triglyceride-rich LD accumulation when overexpressed in cells, mouse liver, or muscle. Unlike the ER-resident diacylglycerol O-acyltransferase family of triglyceride-synthesizing enzymes, FITs do not synthesize triglyceride, but rather partition triglyceride into LDs. The mechanism by which FIT proteins mediate this process has not been determined. A simple hypothesis was tested that FIT proteins bind to triglyceride to mediate LD formation. Here, it is shown that FIT proteins purified in detergent micelles directly bind triolein with specificity and saturation-binding kinetics. A FIT2 gain-of-function mutant that formed larger LDs, FLL(157-9)AAA, showed increased binding to triolein relative to wild-type FIT2, whereas FIT1 and a FIT2 partial loss-of-function mutant, N80A, had significantly lower triolein binding and produced smaller LDs. In summary, FIT proteins are transmembrane domain-containing proteins shown to bind triglyceride. These findings indicate that FITs have a unique biochemical mechanism in mediating LD formation and implicates triglyceride binding as important for FIT-mediated LD formation.ipid droplets are cytosolic structures found in cells of all eukaryotes and are composed of a monolayer of phospholipids surrounding a core of uncharged lipids such as triglyceride (TAG) and sterol esters. These structures are considered organelles largely based on the findings that they contain a unique proteome and are dynamic in nature (1). Lipid droplet (LD) formation involves the partitioning of neutral lipids from their site of synthesis at the endoplasmic reticulum (ER) to the cytosol and is considered to be a rapid process (2). The proteins that mediate the partitioning of triglyceride into LDs have not been previously identified; thus, the mechanism of LD formation is not known. Several forward genetic screens were recently conducted in model organisms and cells to identify proteins important in LD biology. These screens have surprisingly revealed that more than 1% of the genes in eukaryotic genomes are involved in LD biology (3-5), underscoring the importance of the LD in normal cellular physiology. Several members of the perilipin family, namely plin2, plin3, and plin4, have been implicated as having roles in LD formation (6-8). However, most evidence supports a role of the plin family in the regulated lipolysis of LDs (9). Interestingly, the ER-resident membrane protein seipin, which is responsible f...

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“…The Rab9 effector TIP47 binds the cytoplasmic domains of mannose-6-phosphate receptors (MPRs) in a Rab9-GTP-stimulated manner and is required for the return of this cargo to the Golgi complex (Carroll et al 2001). Because TIP47 is also involved in lipid droplet biogenesis under conditions of rapid fat storage, it remains to be determined if TIP47 might be a shared effector that also interacts with one of the myriad of Rab GTPases involved in lipid droplet formation or, alternatively, promotes interorganellar tethering to lipid droplets to allow access to critical lipid regulators of endocytosis Bulankina et al 2009;Hynson et al 2012). Indeed, Tip47 and Rab9 are important targets in viral infectivity and have been associated with lipid droplet consumption, suggesting that resolving this open question will be of significant interest (Murray et al 2005;Chen et al 2009b;Carvalho et al 2012;Vogt et al 2013).…”

Section: Rab Gtpases In Vesicle Buddingmentioning

confidence: 99%

Rab Proteins and the Compartmentalization of the Endosomal System

Wandinger‐Ness

Zerial

2014

Cold Spring Harbor Perspectives in Biology

509

469

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Of the approximately 70 human Rab GTPases, nearly three-quarters are involved in endocytic trafficking. Significant plasticity in endosomal membrane transport pathways is closely coupled to receptor signaling and Rab GTPase-regulated scaffolds. Here we review current literature pertaining to endocytic Rab GTPase localizations, functions, and coordination with regulatory proteins and effectors. The roles of Rab GTPases in (1) compartmentalization of the endocytic pathway into early, recycling, late, and lysosomal routes; (2) coordination of individual transport steps from vesicle budding to fusion; (3) effector interactomes; and (4) integration of GTPase and signaling cascades are discussed.

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TIP47 functions in the biogenesis of lipid droplets

Cited by 237 publications

References 51 publications

The Adipophilin C Terminus Is a Self-folding Membrane-binding Domain That Is Important for Milk Lipid Secretion

The Adipophilin C Terminus Is a Self-folding Membrane-binding Domain That Is Important for Milk Lipid Secretion

Direct binding of triglyceride to fat storage-inducing transmembrane proteins 1 and 2 is important for lipid droplet formation

Rab Proteins and the Compartmentalization of the Endosomal System

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