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bond. Clearly TEP1 targets parasites fordestruction by subsequent lysis or melaniza-tion in both the sensitive and refractory lines(Fig. 1). It is possible that the additionalkilling in the refractory mosquitoes mayrelate to the sequence differences betweenthe different versions of TEP1.

In our urgency to find effective controlmethods for malaria, there is a strong temp-tation to view the importance of this work,and related studies of other components ofthe mosquito’s immune system8, largely interms of likely practical benefit. These stud-ies certainly could lead to better controlmethods involving the selection of refrac-tory mosquitoes through conventionalgenetics or creation the of transgenic mos-quitoes, or even the use of compounds to

specifically upregulate the mosquitoes’innate immunity4. Even without generatingcompletely refractory mosquitoes, a reduc-tion in the average number of oocysts devel-oping in infected mosquitoes may makeother methods of malaria control, such astransmission-blocking vaccines, work muchmore effectively.

However, possible applications of thiswork should not overshadow the interestingand important basic science that these stud-ies are unraveling. The development ofmalaria vaccines has been a significant driv-ing force for a better understanding of adap-tive immunity in the vertebrate host. Malariais one of the few diseases that has exerted astrong enough evolutionarily pressure onhumans that we can readily see its impact

through the presence of genetic markerssuch as sickle-cell anemia. This has allowedthe study of the coevolution of malaria para-sites and their vertebrate hosts. Now, thestudy of malaria in mosquitoes is proving tobe a similarly productive area for under-standing the innate immune system and thecoevolution of parasites and their inverte-brate hosts.

1. Blandin, S. et al. Cell 116, 661–670 (2004).2. Sinden, R.E. Cell Microbiol. 4, 713–724 (2002).3. Holt, R.A. et al. Science 298, 129–149 (2002).4. Christophides, C.K., Vlachou, D. & Kafatos, F.C.

Immunol. Rev. 198, 127–148 (2004).5. Blandin, S. et al. EMBO Rep. 3, 852–856 (2002).6. Levashina, E.A. et al. Cell 104, 709–718 (2001).7. Collins, F.H. et al. Science 234, 607–610

(1986).8. Osta, M.A., Christophides, G.K. & Kafatos, F.C.

Science 303, 2030–2032 (2004).

NATURE MEDICINE VOLUME 10 | NUMBER 5 | MAY 2004 457

A COG in the sugar machineThorsten Marquardt

Defects in a Golgi protein, COG7, underlie a disorder that kills children in the first year of life. The disorder is thefirst to be defined in a class that will likely expand with future studies (pages 518–523).

Metabolic specialists and pediatric neurol-ogists encounter a patient nearly every daywith a severe and life-threatening multisys-tem disease that, despite all efforts, theycannot diagnose. In this issue, Wu andStreet et al.1 provide hope by tracing theunderpinnings of a previously undefineddisorder. The authors describe a congenitaldisorder of glycosylation (CDG), caused bya defect that, among other effects, uniquelydisrupts the machinery that adds sugargroups to proteins. The work shows that asimple blood test, careful examination ofcells and well-designed experiments canlead to the discovery of new diseases, andsuggests that similar approaches may crackmany of these unsolved cases in the future.

Inherited metabolic disorders that affectglycan biosynthesis have been a topic ofintense research since the discovery of thefirst enzymatic defect in 1995 (ref. 2). Sincethen, 15 different disorders (termed CDG)have been discovered in rapid succession3.In most cases, CDG patients are severely illfrom birth, and many die within the firsttwo years of life. The disorders are caused

by a defect of a glycosyltransferase, glycosi-dase or sugar-nucleotide transporterinvolved in the biosynthesis of N- or O-

linked glycans. Since the enzymatic defectsresult in glycoproteins and lipids with miss-ing or structurally abnormal glycans, it is

Thorsten Marquardt is at the University of Münster,

Department of Pediatrics, Albert-Schweitzer-Str. 33,

48149 Münster, Germany.

e-mail: marquat@uni-muenster.de

CDG-IIdCDG-IIa

GlcNActransferase II

FucosyltransferaseVIII

Galactosyl-transferase Sialyltransferase

Asn

UDP-gal CMP-SialGDP-Fuc

Cog1

Cog2

Cog3

Cog4 Cog5

Cog6

Cog8 Cog1

Cog2

Cog3

Cog4 Cog5

Cog6

Cog8

Cog7 Cog7

Golgi

Cytoplasm

CDG-IIc

Figure 1 Glycosylation reactions in the Golgi. Membrane-anchored glycosyltransferases modify the N-glycan bound to asparagine (Asn) residues of the protein. Congenital disorders of glycosylation are designated by a red cross. The conserved oligomeric Golgi (COG)complex is attached to the cytoplasmic surface of the Golgi and keeps glycosyltransferases and sugar nucleotide transporters in place. Disruption of the complex caused by COG7deficiency leads to mislocalization of interacting enzymes and transporters resulting inhypoglycosylation of glycoproteins. Wu and Street et al.1 have found that COG7 deficiencyunderlies a severe multisystem disease that kills children shortly after birth. Blue square = N-acetylglucosamine, red circle = mannose, green rhombus = galactose, red rhombus = sialic acid, gray triangle = fucose.

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Inflammation and bone resorption oftengo hand in hand, a fact evident in condi-tions such as joint destruction in rheuma-toid arthritis or periodontal disease.Osteoclasts, the bone-resorbing cells of theorganism, also share several features withmacrophages and dendritic cells. Osteo-clasts are derived from hematopoietic stemcells within the macrophage lineage, and

they respond to several interleukins produced by activated T cells1,2. Theseinclude receptor activator of NFkB ligand(RANKL) and tumor necrosis factor(TNF), which stimulate osteoclast differen-tiation and bone resorption.

In 15 April issue of Nature, Koga andInui et al.3 tighten the link between boneresorption and the immune system. Theauthors show that cells of the immune sys-tem and osteoclasts share a requirement forcostimulatory signals that are mediated byimmunoreceptor tyrosine-based activationmotifs (ITAMs). In osteoclasts, this costim-ulation is needed for RANKL-induced dif-ferentiation and bone resorption.

N E W S A N D V I E W S

not surprising that these disorders affectmany different organ systems and oftenlead to psychomotor retardation, failure tothrive, cardiomyopathy and many othersymptoms.

Wu and Street et al.1 present a new type of CDG, number 16. It is, however, not just another one of these disorders; its effects appear to extend far beyond glycosylation.

The authors describe two siblings whoboth died within the first 3 months of life.Blood tests revealed abnormal glycosylationin a serum protein used to screen for CDG.Next, the authors examined patient fibrob-lasts and found a small but consistentincrease in the lectin-column binding oflabeled glycopeptides isolated from onepatient’s cells. Further tests revealed multi-ple abnormalities in the activities of varioussugar nucleotide transporters and glycosyl-transferases.

Homing in on the underlying abnormal-ity, the authors found that a glycosyltrans-ferase normally localized to the Golgi didnot reach that location with normal kinet-ics. As has been often the case in the historyof CDG, a similar phenotype found in awell-characterized glycosylation-deficientChinese Hamster ovary (CHO) cell line ledthe way to the discovery of the primarydefect. It involves not another enzyme ortransporter that directly regulates glycosy-lation, but rather a defect of a Golgi pro-tein, COG7.

Like clathrin coats or adaptor proteins,proteins in the COG family are peripherallyattached Golgi coat proteins. The conservedoligomeric Golgi (COG) complex is abilobed, hetero-octameric protein com-plex4 (Fig. 1) with multiple functions. Thecomplex is involved in the retention ofGolgi resident proteins, control of retro-grade Golgi to ER transport and membranetrafficking, intra-Golgi transport, and gly-cosylation.

COG1 and COG2, the first identifiedsubunits, were first examined in glycosyla-tion-deficient CHO mutant cells lines. Thedisruption of the COG complex in thesecells leads to multiple glycosylation abnor-malities5 and numerous morphological andfunctional defects, such as dilated Golgi cis-ternae. Resident Golgi proteins are misclo-calized to the endoplamic reticulum, andshow increased degradation.

Eleven of the 15 types of CDG discoveredso far have been found by investigating theN-glycosylation of proteins, revealing anabnormal glycan structure, or reducedamounts of the glycan, traceable to defects

in glycan synthesis (CDG-I). Only fourtypes of CDG affect the processing of theglycan after its transfer to the protein(CDG-II). This imbalance is mostly due tothe fact that many alterations in CDGpatients suspected to have CDG-II haveturned out to be secondary to an unknownprimary defect. The new discovery1 ushersin a new era of research, as it is the first toimplicate a molecular defect outside of theglycosylation machinery.

In a field where the nomenclature is stillin flux, the currently chosen nomenclatureof COG7 deficiency as CDG-IIe is, as theauthors point out, not optimal. COG7 defi-ciency is not just another member in therapidly growing group of congenital gly-coslyation disorders; it is the first memberin a completely new class. In COG7 defi-ciency, the alteration of glycosylation issecondary to the alteration of a Golgi pro-tein not primarily involved in glycosyla-tion.

Analysis of COG-deficient CHO cells, forinstance, suggests that the glycosylationabnormalities result from the mislocaliza-tion of resident Golgi enzymes and trans-porters involved in glycosylation; proteinsnot involved in glycosylation are also mislo-calized6. It is likely that further analysis ofCOG7-deficient cells will show a similar pic-

ture. Similarly, in the two COG7-deficientpatients, the severe phenotype may becaused only in part by glycosylation abnor-malities.

COG7 deficiency represents a new classof diseases affecting coat proteins associ-ated with the cytoplasmic surface oforganelles and involved in intracellulartrafficking. In this respect, COG7 defi-ciency is comparable to diseases such asChediak-Higashi or Hermansky-Pudlakdisease; this group of disorders affects dif-ferent coat proteins later on in the secre-tory pathway, although, clinically, thesymptoms do not resemble COG7 defi-ciency.

It is to be expected that this new group of‘coat’ diseases, which includes COG7 deficiency, will grow just as rapidly as theCDG group has in the last ten years.After all, the simple blood test used toscreen for CDG is likely to yield a few moresurprises.

1. Wu, X. et al. Nat. Med. 10, 518–523 (2004).2. Van Schaftingen, E. & Jaeken, J. FEBS Lett. 377,

318–320 (1995).3. Marquardt, T. & Denecke, J. Eur. J. Pediatr. 163,

359–379 (2003).4. Ungar, D. et al. J. Cell Biol. 157, 405–415

(2002).5. Kingsley, D.M. et al. J. Cell Biol. 102, 1576–1585

(1986).6. Oka, T. et al. Mol. Biol. Cell (in press).

458 VOLUME 10 | NUMBER 5 | MAY 2004 NATURE MEDICINE

Arming the osteoclastRoland Baron

Signaling through costimulatory receptors classically occurs in cells ofthe immune system. Now the distinction between immune cells andosteoclasts, bone resorbing cells, begins to blur. Osteoclasts needcostimulatory signals too.

Roland Baron is in the Departments of Cell Biology

and Orthopedics, Yale University School of

Medicine, 333 Cedar Street, New Haven,

Connecticut 06510, USA.

e-mail: roland.baron@yale.edu

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