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PubMed2006

ARF proteins: roles in membrane traffic and beyond.

The ADP-ribosylation factor (ARF) small GTPases regulate vesicular traffic and organelle structure by recruiting coat proteins, regulating phospholipid metabolism and modulating the structure of actin at membrane surfaces. Recent advances in our understanding of the signalling pathways that are regulated by ARF1 and ARF6, two of the best characterized ARF proteins, provide a molecular context for ARF protein function in fundamental biological processes, such as secretion, endocytosis, phagocytosis, cytokinesis, cell adhesion and tumour-cell invasion.

ADP-Ribosylation Factors↗
PubMed2003

Molecular mechanism of membrane recruitment of GGA by ARF in lysosomal protein transport.

GGAs are critical for trafficking soluble proteins from the trans-Golgi network (TGN) to endosomes/lysosomes through interactions with TGN-sorting receptors, ADP-ribosylation factor (ARF) and clathrin. ARF-GTP bound to TGN membranes recruits its effector GGA by binding to the GAT domain, thus facilitating recognition of GGA for cargo-loaded receptors. Here we report the X-ray crystal structures of the human GGA1-GAT domain and the complex between ARF1-GTP and the N-terminal region of the GAT domain. When unbound, the GAT domain forms an elongated bundle of three a-helices with a hydrophobic core. Structurally, this domain, combined with the preceding VHS domain, resembles CALM, an AP180 homolog involved in endocytosis. In the complex with ARF1-GTP, a helix-loop-helix of the N-terminal part of GGA1-GAT interacts with the switches 1 and 2 of ARF1 predominantly in a hydrophobic manner. These data reveal a molecular mechanism underlying membrane recruitment of adaptor proteins by ARF-GTP.

ADP-Ribosylation Factor 1↗
PubMed2005

Developmental specificity of auxin response by pairs of ARF and Aux/IAA transcriptional regulators.

The plant hormone auxin elicits many specific context-dependent developmental responses. Auxin promotes degradation of Aux/IAA proteins that prevent transcription factors of the auxin response factor (ARF) family from regulating auxin-responsive target genes. Aux/IAAs and ARFs are represented by large gene families in Arabidopsis. Here we show that stabilization of BDL/IAA12 or its sister protein IAA13 prevents MP/ARF5-dependent embryonic root formation whereas stabilized SHY2/IAA3 interferes with seedling growth. Although both bdl and shy2-2 proteins inhibited MP/ARF5-dependent reporter gene activation, shy2-2 was much less efficient than bdl to interfere with embryonic root initiation when expressed from the BDL promoter. Similarly, MP was much more efficient than ARF16 in this process. When expressed from the SHY2 promoter, both shy2-2 and bdl inhibited cell elongation and auxin-induced gene expression in the seedling hypocotyl. By contrast, gravitropism and auxin-induced gene expression in the root, which were promoted by functionally redundant NPH4/ARF7 and ARF19 proteins, were inhibited by shy2-2, but not by bdl protein. Our results suggest that auxin signals are converted into specific responses by matching pairs of coexpressed ARF and Aux/IAA proteins.

Arabidopsis↗
PubMed2001

One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus.

The INK4A/ARF/INK4B locus, conserved in mammals, encodes three polypeptides that regulate cell proliferation via the pRb and p53 tumour suppressor pathways. The locus is mutated in many cancers. The related, tandemly-linked INK4A and INK4B genes encode the p16(INK4A) and p15(INK4B) members of the INK4 family of cyclin-dependent kinase inhibitors which block phosphorylation of pRb, whereas the third product, ARF, derived from an alternative reading frame of INK4A, regulates p53 activity. We assessed the status of this unusual locus in the puffer fish, Fugu rubripes, and identified two INK4 genes using degenerate PCR and hybridization analyses. Sequence conservation and conservation of synteny between human and Fugu predict one gene to be an INK4A or INK4B homologue and the other an INK4D homologue. Analysis of the Fugu INK4A/B gene and the surrounding 40-kb of genomic DNA did not reveal the presence of any ARF-encoding potential or another related INK4 gene. We conclude that the gene duplication event that generated adjacent INK4A and INK4B genes and the association of ARF with the ancestral INK4A gene occurred after the divergence of the lineage leading to mammals from fish. Thus, unlike mammals, the fish p53 and pRb tumour suppressor pathways are not regulated by a single locus.

Amino Acid Sequence↗
PubMed2004

Overexpression of leukocyte marker CD43 causes activation of the tumor suppressor proteins p53 and ARF.

CD43 or leukosialin is a transmembrane sialoglycoprotein, whose extracellular domain participates in cell adhesiveness and the cytoplasmic tail regulates a variety of intracellular signal transduction pathways involved in cell proliferation. CD43 is abundantly expressed on the surface of hematopoietic cells, but CD43 expression is also frequently found in the tumor cells of nonhematopoietic origin. In the early stages of some tumors, the accumulation of tumor suppressor protein p53 has been described. Here, we show that the expression of CD43 causes the induction of functionally active p53 protein. Moreover, we found that the activation of p53 by CD43 is mediated by tumor suppressor protein ARF. The coexpression of CD43 and ARF in ARF-null mouse embryonic fibroblasts resulted in programmed cell death, but that was not the case when CD43 alone was expressed in these cells. These data provide the first evidence of the connection between p53- and CD43-dependent pathways.

ADP-Ribosylation Factor 1↗
PubMed2005

On the action of Brefeldin A on Sec7-stimulated membrane-recruitment and GDP/GTP exchange of Arf proteins.

Arf (ADP-ribosylation factor) proteins form a special class of small GTP-binding proteins in that their activation by GDP/GTP exchange is coupled to their recruitment to membranes using a built-in structural mechanism. These coupled processes are stimulated by GEFs (guanine nucleotide-exchange factors) that carry a catalytic Sec7 domain, whose basic mechanism has been uncovered by biochemical and structural studies. Crystal structures of intermediates of the GDP/GTP exchange reaction, from which GDP has not dissociated, notably allowed a movie of the exchange reaction to be reconstituted. They showed that Sec7 domains secure Arf-GDP to membranes before they proceed to nucleotide dissociation, and thus are active participants to the coupling of membrane-recruitment to nucleotide exchange. The drug BFA (Brefeldin A) was used to trap the complex that initiates the exchange reaction, providing a structural basis for its inhibition of Arf and its action on the membrane-recruitment of isolated Sec7 domains. Based on the dissection of this basic mechanism, the survey of reported BFA effects in cells on large multidomain ArfGEFs of the BIG1/2 and GBF1 families shows that the levels and compartmental distribution of BFA-induced recruitment of ArfGEFs to membranes cannot be explained from isolated Sec7 domains acting as independent domains. This leads to the hypothesis that Sec7 activity is inhibited in these ArfGEFs by an intramolecular interaction, which would be released by interaction with a compartment-specific receptor.

ADP-Ribosylation Factors↗
PubMed2005

Arfs, phosphoinositides and membrane traffic.

Arf (ADP-ribosylation factor) GTP-binding proteins function in cells to regulate membrane traffic and structure. Arfs accomplish this task through modification of membrane lipids and the recruitment of proteins, including coat proteins and actin, to membrane surfaces. Arf1 and Arf6 are the most divergent and most studied human Arf proteins that localize predominantly to the Golgi complex and plasma membrane respectively. We have been studying the targeting of Arf1 and Arf6 to these specific compartments and the common and divergent activities that they exert on these membranes. We have found that Arf6 acts through activation of type I phosphatidylinositol 4-phosphate 5-kinases to generate phosphatidylinositol 4,5-bisphosphate and that this activity is instrumental in facilitating the actin cytoskeletal rearrangements and alterations in endosomal membrane trafficking observed with increased Arf6 activation. Arf1 can also stimulate the activity of phosphatidylinositol kinases and recruit coat proteins and actin cytoskeletal elements to the Golgi complex.

ADP-Ribosylation Factor 1↗
PubMed2003

ICAM-1 expression and leukocyte accumulation in inner stripe of outer medulla in early phase of ischemic compared to HgCl2-induced ARF.

BACKGROUND: After ischemia/reperfusion (I/R), as well as after toxic insults, there is significant infiltration of leukocytes in the kidney. It is well known that antibodies against adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1)] protect the kidney against acute ischemic injury. In contrast, same antibody treatment did not protect the rat kidney against toxic acute renal failure (ARF) induced by HgCl2. Protection obtained by anti-adhesion treatment in I/R injury is an early phenomenon, since delaying the administration of anti-ICAM-1 for 8 hours did not protect the kidney anymore. The aim of this study was to compare the early ICAM-1 expression and leukocyte accumulation in different zones of ischemic and toxic injury. METHODS: Male Lewis rats were injected with HgCl2 (2 mg/kg, subcutaneously) or uninephrectomized Lewis rats were submitted to 30 degrees C warm ischemia (I/R injury). Rats were sacrificed at 2, 6, 12 and 24 hours. ICAM-1 (1A29) expression in kidney was evaluated morphometrically. Different subsets of leukocytes were stained by immunohistochemistry and counted in cortex, the outer stripe of the outer medulla (OSOM) and the level of the inner stripe of the outer medulla (ISOM). RESULTS: Although the functional and morphologic damage was comparable between the I/R and toxic ARF group, different ICAM-1 expression could be observed early after injury. ICAM-1 expression in the ISOM started already 2 hours after the onset of I/R injury, and was increased after 12 hours in the cortex and after 24 hours in the OSOM. In contrast, during the first 24 hours after injury, ICAM-1 expression in HgCl2-injured kidneys was not different from noninjured kidneys in the ISOM and the cortex, whereas in the OSOM, ICAM-1 expression increased. The number of polymononuclear cells (PMNs) was low in noninjured kidneys and did not increase in time after both I/R injury and after HgCl2-induced ARF. In the ISOM, significant monocyte and T-cell accumulation was observed early after I/R but not after HgCl2. There was no significant T-cell accumulation in the cortex or in the OSOM. CONCLUSION: After HgCl2, almost no leukocyte accumulation and up-regulation of ICAM-1 was observed the first 12 hours after injury. In contrast, very early after I/R injury, increased expression of ICAM-1 goes along with monocyte and T-cell accumulation in the ISOM, endorsing this particular zone as critical in renal I/R injury. These observations contribute to the understanding why anti-ICAM-1 treatment in acute I/R injury is successful, but fails in acute toxic injury induced by HgCl2.

Acute Kidney Injury↗
PubMed2003

Hand-assisted laparoscopic radical nephrectomy-associated rhabdomyolysis with ARF.

Intraoperative rhabdomyolysis with resultant acute renal failure is a rare complication seen, most commonly, with urologic surgical procedures. Since the early 1990s, the refinement of laparoscopic techniques has permitted their application more broadly. Among the procedures to benefit from these less invasive surgical methods has been radical nephrectomy. In general, this has resulted in less postoperative pain and shorter convalescence. Nonetheless, laparoscopic radical nephrectomy still represents major surgery and is not free from operative risks. To highlight one of these risks, we present a case of a young, obese man with renal cell carcinoma who underwent a hand-assisted laparoscopic radical nephrectomy that was complicated by rhabdomyolsis resulting in acute renal failure (ARF). We discuss the clinical insults that contributed to the development of azotemia with particular attention paid to our current understanding of the pathogenesis of myoglobinuric ARF. In addition, we review the literature concerning surgery-associated, rhabdomyolytic ARF with the aim of providing clinicians guidance for the avoidance and early recognition of this rare, but very serious, surgical complication.

Acute Kidney Injury↗
PubMed2004

ARF in children with minimal change nephrotic syndrome may be related to functional changes of the glomerular basal membrane.

BACKGROUND: Acute renal failure (ARF) is a rare complication in children with minimal change nephrotic syndrome (MCNS). Several etiologic factors (renal vein thrombosis, side effect of such drugs as nonsteroidal anti-inflammatory drugs, and infections) have been described, but often such conditions are lacking, and hemodynamic derangements or changes in glomerular permeability are suspected. METHODS: We assessed the role of alterations in renal perfusion and glomerular permeability by measuring clearances of inulin and para-aminohippurate before and during intravenous administration of a 20% albumin solution in patients with MCNS and oliguric ARF (serum creatinine > 1 mg/dL [88 micromol/L], urine output < 0.5 mL/kg body weight/h). RESULTS: Eleven patients aged 2.5 to 15 years with biopsy-proven MCNS were studied. Before albumin administration, all patients had a significantly decreased glomerular filtration rate (GFR), whereas most renal plasma flow (RPF) values were within the normal range. This resulted in a significantly decreased filtration fraction (FF; GFR/RPF x 100), which was extremely low (<7%) in 4 patients. There was a heterogeneous response to albumin administration. Albumin infusion tended to increase RPF, but changes did not reach statistical significance. Some patients showed an increase in glomerular filtration, whereas in others, it decreased. In 7 patients, FF remained unchanged or decreased even further. CONCLUSION: Our data suggest that, although in some patients decreased intravascular volume may contribute to reduced renal function, changes in glomerular permeability may have a major role in ARF occurring in uncomplicated MCNS.

Acute Kidney Injury↗
PubMed2004

A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF.

BACKGROUND: Despite the widespread use of continuous renal replacement therapy in critically ill patients with acute renal failure (ARF), there are few data supporting its benefits over conventional intermittent hemodialysis (IHD). We sought to analyze differences in survival between modalities in a study that compared continuous venovenous hemodialysis (CVVHD) with IHD. METHODS: Eighty critically ill patients with ARF requiring dialysis were randomized after stratification by severity of illness to treatment with CVVHD or IHD. RESULTS: There were no differences in survival or renal recovery between groups. In patients who died, mean survival time was 10.7 +/- 11.2 days for the IHD group versus 14.3 +/- 16.1 days for the CVVHD group (P = not significant). There was greater net volume removal in the CVVHD group during 72 hours. Declines in urine output during 72 hours were similar between groups. Mean arterial pressure off and on dialysis therapy was analyzed retrospectively. There was a significant decrease in mean arterial pressure for patients on IHD therapy not seen in those on CVVHD therapy, but this did not lead to a survival advantage. CONCLUSION: Despite greater volume control, CVVHD did not lead to an improvement in survival, preservation of urine output, or renal recovery compared with IHD in patients with ARF.

Acute Kidney Injury↗
PubMed2026

Auxin-induced ARF transcription factor degradation defines tissue boundaries.

How organs partition themselves into discrete domains with distinct functions is a fundamental question in biology. The gynoecium of flowering plants provides an excellent system to address this question. Here, we show that the boundary between the stigma and style at the gynoecium apex is established by the complementary distribution of the phytohormone auxin and the Auxin Response Factor (ARF), ETTIN (ETT). Mechanistically, auxin induces ETT protein destabilization via the ubiquitin-proteasome pathway. A short sequence motif within an intrinsically disordered region is required for this auxin-triggered degradation. Disruption of this motif leads to ectopic ETT accumulation at the gynoecium apex and consequently abolishes stigma-style boundary development. We further demonstrate that this previously unrecognized mode of auxin-induced ARF instability is evolutionarily conserved among ETT orthologs across angiosperms. In summary, this study reveals how graded auxin distribution affects ARF transcription factor activity, contributing to the establishment of the stigma-style boundary, ensuring correct gynoecium formation and reproductive success in flowering plants.

Indoleacetic Acids↗
PubMed1996

Isolation of a brefeldin A-inhibited guanine nucleotide-exchange protein for ADP ribosylation factor (ARF) 1 and ARF3 that contains a Sec7-like domain.

Brefeldin A (BFA) inhibited the exchange of ADP ribosylation factor (ARF)-bound GDP for GTP by a Golgi-associated guanine nucleotide-exchange protein (GEP) [Helms, J.B. & Rothman, J.E. (1992) Nature (London) 360, 352-354; Donaldson, J.G., Finazzi, D. & Klausner, R.D. (1992) Nature (London) 360, 350-352]. Cytosolic ARF GEP was also inhibited by BFA, but after purification from bovine brain and rat spleen, it was no longer BFA-sensitive [Tsai, S.-C., Adamik, R., Moss, J. & Vaughan, M. (1996) Proc. Natl. Acad. Sci. USA 93, 305-309]. We describe here purification from bovine brain cytosol of a BFA-inhibited GEP. After chromatography on DEAE-Sephacel, hydroxylapatite, and Mono Q and precipitation at pH 5.8, GEP was eluted from Superose 6 as a large molecular weight complex at the position of thyroglobulin (approximately 670 kDa). After SDS/PAGE of samples from column fractions, silver-stained protein bands of approximately 190 and 200 kDa correlated with activity. BFA-inhibited GEP activity of the 200-kDa protein was demonstrated following electroelution from the gel and renaturation by dialysis. Four tryptic peptides from the 200-kDa protein had amino acid sequences that were 47% identical to sequences in Sec7 from Saccharomyces cerevisiae (total of 51 amino acids), consistent with the view that the BFA-sensitive 200-kDa protein may be a mammalian counterpart of Sec7 that plays a similar role in cellular vesicular transport and Sec7 may be a GEP for one or more yeast ARFs.

ADP-Ribosylation Factors↗
PubMed1995

Different ARF domains are required for the activation of cholera toxin and phospholipase D.

ADP-ribosylation factors (ARFs), initially described as activators of cholera toxin ADP-ribosyltransferase activity, regulate intracellular vesicular membrane trafficking and stimulate a phospholipase D (PLD) isoform. ARF-like (ARL) proteins are structurally related to ARFs but do not activate cholera toxin and have relatively little effect on PLD. A new human ARL gene termed hARL1, which shares 57% amino acid identity with hARF1, was identified using a polymerase chain reaction-based cloning method. To determine whether different structural elements are responsible for the activation structural elements are responsible for the activation of the A subunit of cholera toxin and PLD, chimeric proteins were constructed by switching the amino-terminal 73 amino acids of ARF1 and ARL1. The recombinant rL73/F protein, in which the amino-terminal 73 amino acids of ARL1 replaced those of ARF1, activated the A subunit of cholera toxin, whereas the rF73/L protein, in which the NH2-terminal 73 amino acids of ARF1 replaced those of ARL1, was inactive. The two chimeric proteins had quite opposite effects on PLD activity. rF73/L activated PLD as effectively as rARF1, whereas rL73/F protein activated PLD only slightly. It appears that the amino-terminal region of ARF1 is not critical for its action as a GTP-dependent activator of cholera toxin, whereas it is necessary for activation of the putative effector enzyme, PLD.

ADP-Ribosylation Factor 1↗
PubMed2000

ARL4, an ARF-like protein that is developmentally regulated and localized to nuclei and nucleoli.

ADP-ribosylation factors (ARFs) are highly conserved approximately 20-kDa guanine nucleotide-binding proteins that participate in both exocytic and endocytic vesicular transport pathways via mechanisms that are only partially understood. Although several ARF-like proteins (ARLs) are known, their biological functions remain unclear. To characterize its molecular properties, we cloned mouse and human ARL4 (mARL4 and hARL4) cDNA. The appearance of mouse ARL4 mRNA during embryonic development coincided temporally with the sequential formation of somites and the establishment of brain compartmentation. Using ARL4-specific antibody for immunofluorescence microscopy, we observed that endogenous mARL4 in cultured Sertoli and neuroblastoma cells was mainly concentrated in nuclei. When expressed in COS7 cells, ARL4-T34N mutant, predicted to exist with GDP bound, was concentrated in nucleoli. Yeast two-hybrid screening and in vitro protein-interaction assays showed that hARL4 interacted with importin-alpha through its C-terminal NLS region and that the interaction was not nucleotide-dependent. Like ARL2 and -3, recombinant hARL4 did not enhance cholera toxin-catalyzed auto-ADP-ribosylation. Its binding of guanosine 5'-O-(thiotriphosphate) was modified by phospholipid and detergent, and the N terminus of hARL4, like that of ARF, was myristoylated. Our findings suggest that ARL4, with its distinctive nuclear/nucleolar localization and pattern of developmental expression, may play a unique role(s) in neurogenesis and somitogenesis during embryonic development and in the early stages of spermatogenesis in adults.

ADP-Ribosylation Factors↗
PubMed2001

Structures of yeast ARF2 and ARL1: distinct roles for the N terminus in the structure and function of ARF family GTPases.

Structures were determined by x-ray crystallography for two members of the ADP-ribosylation factor (ARF) family of regulatory GTPases, yeast ARF1 and ARL1, and were compared with previously determined structures of human ARF1 and ARF6. These analyses revealed an overall conserved fold but differences in primary sequence and length, particularly in an N-terminal loop, lead to differences in nucleotide and divalent metal binding. Packing of hydrophobic residues is central to the interplay between the N-terminal alpha-helix, switch I, and the interswitch region, which along with differences in surface electrostatics provide explanations for the different biophysical and biochemical properties of ARF and ARF-like proteins.

ADP-Ribosylation Factors↗
PubMed2003

Functional and physical interaction of the human ARF tumor suppressor with Tat-binding protein-1.

The p14ARF tumor suppressor is a key regulator of cellular proliferation, frequently inactivated in human cancer, whose mode of action is currently not completely understood. We report here that the so-called human immunodeficiency virus Tat-binding protein-1 (TBP-1), a component of the 19 S regulatory subunit of the proteasome 26 S, also involved in transcriptional regulation and with a supposed role in the control of cell proliferation, specifically interacts with ARF, both in yeast and mammalian cells. We present evidence that the overexpression of TBP-1 in various cell lines results in a sharp increase of both transfected and endogenous ARF protein levels. Moreover, this effect depends on the binding between the two proteins and, at least in part, is exerted at the post-translational level. We also show that the ARF increase following TBP-1 overexpression results in an increase in p53 protein levels and activity. Finally, our data underline a clear involvement of TBP-1 in the control of cell proliferation.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2006

Dual specificity of the interfacial inhibitor brefeldin a for arf proteins and sec7 domains.

Guanine nucleotide exchange factors (GEFs), which activate small GTP-binding proteins (SMG) by stimulating their GDP/GTP exchange, are emerging as candidate targets for the inhibition of cellular pathways involved in diseases. However, their specific inhibition by competitive inhibitors is challenging, because GEF and SMG families comprise highly similar members. Nature shows us an alternative strategy called interfacial inhibition, exemplified by Brefeldin A (BFA). BFA inhibits the activation of Arf1 by its GEFs in vivo by stabilizing an abortive complex between Arf-GDP and the catalytic Sec7 domain of some of its GEFs. Here we characterize the specificity of BFA toward wild-type (ARNO and BIG1) and mutant Sec7 domains and toward class I, II, and III Arfs. We find that BFA sensitivity of the exchange reaction depends on the nature of both the Sec7 domain and the Arf protein. A single Phe/Tyr substitution is sufficient to achieve BFA sensitivity of the Sec7 domain, which is supported by our characterization of brefeldin C (BFC), a BFA analog that cannot interact with the Tyr residue, and by free energy computations. We further show that Arf1 and Arf5, but not Arf6, are BFA-sensitive, despite their having every BFA-interacting residue in common. Analysis of Arf6 mutants points to the dynamics of the interswitch, which is involved in membrane-to-nucleotide signal propagation, as contributing to, although not sufficient for, BFA sensitivity. Altogether, our results reveal the Tyr/Phe substitution as a novel tool for monitoring BFA sensitivity of cellular ArfGEFs and document the exquisite and dual specificity that can be achieved by an interfacial inhibitor.

ADP-Ribosylation Factors↗