Mic oo ganisms2020,8,357;doi:10.3390/mic oo ganisms8030357www.mdpi.com/jou nal/mic oo ganisms
Re iew
TypeIIISec e ionE ec o swi hA ginine
N‐Glycosyl ans e aseAc i i y
JuanLuisA aujo‐Ga ido,JoaquínBe nal‐Baya dandF anciscoRamos‐Mo ales*
Depa amen odeGené ica,Facul addeBiología,Uni e sidaddeSe illa,41012Se illa,Spain;
[email p o ec ed](J.L.A.‐G.)[email p o ec ed](J.B.‐B.)
*Co espondence:[email p o ec ed]
Recei ed:12Feb ua y2020;Accep ed:29Feb ua y2020;Published:2Ma ch2020
Abs ac :TypeIIIsec e ionsys emsa eusedbymanyG am‐nega i ebac e ialpa hogens oinjec
p o eins,knownase ec o s,in o hecy osolo hos cells.These i ulence ac o sin e e ewi ha
di e sea ayo hos signal ansduc ionpa hwaysandcellula p ocesses.Manye ec o sha e
ca aly icac i i ies op omo epos ‐ ansla ionalmodi ica ionso hos p o eins.This e iew ocuses
ona amilyo e ec o swi hglycosyl ans e aseac i i y ha ca alyzeaddi iono N‐ace yl‐
D
‐
glucosamine ospeci ica ginine esiduesin a ge p o eins,leading o educedNF‐κBpa hway
ac i a ionandimpai edhos celldea h.This amilyincludesNleB omCi obac e oden ium,NleB1
andNleB2 omen e opa hogenicanden e ohemo hagicEsche ichiacoli,andSseK1,SseK2,and
SseK3 omSalmonellaen e ica.Fi s ,weplace hesee ec o sin hegene al amewo ko he
glycosyl ans e asesupe amilyandin hepa icula con ex o he oleo glycosyla ioninbac e ial
pa hogenesis.Then,wep o idede ailedin o ma ionabou cu en lyknownmembe so his
amily, hei olein i ulence,and hei a ge s.
Keywo ds:glycosyl ans e ases; ypeIIIsec e ion;e ec o s;NleB;SseK;Ci obac e ;Esche ichia;
Salmonella;dea hdomains
1.In oduc ion
TypeIIIsec e ionsys ems(T3SSs)a e undamen al ools o hein e ac ionbe weenmany
pa hogenicandsymbio icG am‐nega i ebac e iaand hei hos s.T3SSs,alsoknownasinjec isomes,
span hebac e ialinne andou e memb anesand o minjec ionnanomachines ha deli e p o eins,
knownase ec o s,in o a ge euka yo iccells omodula ea a ie yo cellula unc ions[1,2].
E ec o sha edi e seac i i iesand a ge s,and ypicallyha eanN‐ e minalsec e iondomainand
oneo mo eC‐ e minal unc ionaldomains[3,4].E ec o scanbeclassi iedin ou non‐mu ually
exclusi eca ego iesacco ding o hei mechanismso ac i i y[5]:(i)e ec o s ha media e hei
ac i i ies h oughphysicalin e ac ionswi hhos a ge s;(ii)e ec o s ha use unc ionalo s uc u al
mimic y oal e hos cellp ocesses;(iii)e ec o s ha p omo epos ‐ ansla ionalmodi ica ionso
hos p o eins;and(i )e ec o swi hp o easeac i i y.Exampleso ca aly icac i i ieso e ec o sa e
ubiqui ina ion,deubiqui ina ion,phospho yla ion,dephospho yla ion,ace yla ion,deamida ion,
ADP ibosyla ion,cys eineme hyla ion,andglycosyla ion.This e iew ocusesonaspeci ic amily
o T3SSe ec o swi hglycosyl ans e aseac i i y ha a e oundinSalmonellaen e icaandin
a aching/e acing(A/E)pa hogens.
Salmonellaea e acul a i ein acellula G am‐nega i ebac e ialpa hogensbelonging o he
amilyEn e obac e iaceae.ThegenusSalmonellaincludes hespeciesS.bongo iandS.en e ica, he
la e di idedin osixsubspeciesandmo e han2500se o a s[6].S.en e icapossesses wo i ulence‐
ela edT3SS[7–9],T3SS1andT3SS2, ha a eencodedbySalmonellapa hogenici yisland1(SPI1)and
Salmonellapa hogenici yisland2(SPI2)(Figu e1), espec i ely,whe easS.bongo ilacksSPI2[10].
Mic oo ganisms2020,8,3572o 23
TheT3SS1 ansloca ese ec o sac oss hehos cellplasmamemb ane ha p omo eSalmonella
in asionin oepi helialcellsin hein es ineands imula elocalizedin lamma ion[11].TheT3SS2is
exp essedin acellula lyin esponse oacidicpHandnu ien limi a ion oundin helumeno he
Salmonella‐con aining acuole(SCV),amodi iedphagolysosomewhichis he ypicalin acellula
nicheo hispa hogen[12].T3SS2e ec o sa e ansloca ed h ough heSCVmemb ane,a e
impo an inin es inalanddissemina edin ec ions,anda e equi ed o g ow hwi hindi e en hos
cell ypes[13].Toge he ,T3SS1andT3SS2sec e emo e han40e ec o s,someencodedbySPI1o
SPI2,bu mos encodedou side heseislands,ino he ho izon allyacqui ed egionso hegenome
[14–17].
En e ohemo hagicEsche ichiacoli(EHEC)anden e opa hogenicE.coli(EPEC)a eex acellula
humanpa hogens ha a ach o hein es inalepi heliumande aceb ushbo de mic o illi o ming
A/Elesions[18].EHECcauseshemo hagiccoli isandhemoly icu emicsynd ome,whe easEPEC
isacauseo in an iledia hea.Ci obac e oden iumisano he A/Epa hogenwhichis hecausa i e
agen o mu ine ansmissiblecolonichype plasia[19].LesionsinducedbyC. oden iuminmicea e
simila o hosecausedbyEHECo EPECinhumansand hesepa hogenssha eanumbe o
i ulencede e minan sincluding helocuso en e ocy ee acemen (LEE)[20,21](Figu e1).TheLEE
isa34kbpa hogenici yislandwi h41genes ha encodeall hes uc u alcomponen so aT3SS,
se eno i se ec o sand hei chape ones,p o einsin ol edinadhe ence,and egula o yp o eins
[22].Manye ec o sa eencodedou side heLEE,and he o alnumbe o e ec o sisa leas 29inC.
oden ium,22inEPEC,and39inEHEC[22].Asecondgeneclus e ,po en iallyencodingaT3SSand
knownasETT2, o E.coliT3SS2,isp esen inmanyE.colis ains[23,24].ETT2 esembles he
SalmonellaT3SS1bu inmos casesi hasbeensubjec ed omu a ionala i ionand he eisno
e idence o hesec e iono e ec o sby hissys em[25].Howe e , his egionisin ac insome
s ainso E.coliandEsche ichiaalbe ii,andappea s obeimpo an o bac e ialpa hogenesis[25–
27].
Figu e1.Gene ics uc u eo Salmonellapa hogenici yisland1(SPI1)andSalmonellapa hogenici y
island2(SPI2)o S.en e icase o a Typhimu iums ain14028,and helocuso en e ocy ee acemen
(LEE)islando E.coliO127:H6s ainE2348/69.Genesa ecolo edacco ding o hei unc ional
ca ego ies[22,28].
Mic oo ganisms2020,8,3573o 23
2.Glycosyl ans e ases
Glycosyl ans e ases(GTs)ca alyze he o ma iono glycosidebondsusinganac i a eddono
suga subs a e ha con ainsanucleosidephospha eo alipidphospha elea ingg oup[29].
Enzymes ha usesuga mono‐o diphosphonucleo idesasdono sa eknownasLeloi GTs[30].
Non‐Leloi GTsusenon‐nucleo idedono s,suchaspolyp enolpy ophospha es,polyp enol
phospha es,suga ‐1‐phospha es,o suga ‐1‐py ophospha es.Suga scanbe ans e ed oa a ie y
o biomoleculesincludingglycans,lipids,p o eins,pep ides,andsmallmolecules.The esul ing
glycosidiclinkagecanbeanO‐,S‐,N‐o C‐co alen bondconnec ingamonosaccha ide oano he
esidue.
2.1.Classi ica ion
T adi ionally,GTswe eclassi iedon hebasiso hei dono ,accep o ,andp oduc speci ici y,
acco ding o he ecommenda ionso heIn e na ionalUniono Biochemis yandMolecula Biology
(IUBMB),unde heEnzymeCommissionnumbe EC.2.4.Gi en helimi a ionso hissys em,anew
scheme ha in ol es heclassi ica iono GTsin o amilieson hebasiso aminoacidsequence
simila i iesisnowaccep ed[31,32].Today, heca bohyd a eac i eenzymes(CAZy)da abase
(h p://www.cazy.o g)includeso e 620,000GTmodulesclassi iedinmo e han100 amiliesand
mo e han13,000nonclassi iedmodules.
Dependingon hei mechanismo ans e ,GTscanbeclassi iedasin e ingo e aining,
esul inginin e sion(α‐>β)o e en ion(α‐>α)o hes e eochemis yo hedono ’sanome ic
bonddu ing he ans e , espec i ely[33].Theo e icalandexpe imen als udiessuppo asingle‐
displacemen SN2(subs i u ion,nucleophilic,bimolecula )‐likemechanism o in e ingGTs[29].
Thismechanismin ol es he o ma iono anoxoca beniumion ansi ions a e(Figu e2).Incon as ,
he eac ionmechanismo e ainingglycosyla ioniscon o e sial[34].Adouble‐displacemen
mechanism,inwhich hesuga is i s ans e ed o heenzymeand hen ans e ed o heaccep o ,
wassugges edbyanalogy o e ainingglycosidases[35].Someexpe imen alsuppo wasp o ided
o hismechanism[36,37],pa icula ly o heGT6 amilymembe s ha ha eaca boxyla ep ope ly
o ien ed oac asaca aly icnucleophile.Bu hisisno hecase o mos e ainingGTs,leading o he
p oposalo anal e na i ein e nal e u nSNi(subs i u ion,nucleophilic,in e nal)‐likemechanism,
also e med on ‐ acemechanism,inwhich henucleophilichyd oxyg oupo heaccep o a acks
heanome icca bona om om hesameside omwhich helea ingg oupdepa s[38,39].An
o hogonalmechanismhasalsobeenp oposed ha di e s om heSNimechanismin he eac ion
p o ileand he imeo bond o ma ionandb eakage[40](Figu e2).
Figu e2.Glycosyl ans e asemechanisms.AnSN2(subs i u ion,nucleophilic,bimolecula )p ocessis
accep ed o in e ingglycosyl ans e ases(GTs).Se e almechanismsha ebeenp oposed o
e ainingenzymes.Theo hogonalmechanismisdepic edhe e.‡:T ansi ions a e.ImagebyD .
Mic oo ganisms2020,8,3574o 23
B ockSchumann(WikimediaCommons,CCBY‐SA3.0,h ps://c ea i ecommons.o g/licenses/by‐
sa/3.0/deed.en).
2.2.S uc u alS udies
GTs uc u es(Figu e3) e ealed ha hemajo i yo heseenzymes allin o wogene al olds,
calledGT‐AandGT‐B,eacho whichincludesmembe s ha a e e ainingandin e ingGTs.This
led oaclassi ica iono GTsin ou clans:clanI o in e ingenzymeswi h heGT‐A old,clanII o
in e ingenzymeswi h heGT‐B old,clanIII o e ainingenzymeswi h heGT‐A old,andclanIV
o e ainingenzymeswi h heGT‐B old[32].Bo h old ypescon ainaRossmann old[41],a
nucleo ide‐bindingdomain esponsible o dono nucleo ide ecogni ion.Aseconddomainisusually
esponsible o accep o ecogni ionandismo e a iable.Enzymeswi h heGT‐B ype oldcon ain
woRossmann‐like oldssepa a edbyadeepwidec e ice[42].Howe e ,no allGTs i in o hese
clans.A hi d old ype,calledGT‐C old,wasp edic edusingcompu a ionalme hods[43–45],and
hes uc u eo se e alGTswi h his old,mos o hembelonging o amilyGT66,ha ebeen
desc ibed[46].TheseGTsusuallycon ainanN‐ e minal ansmemb anedomainandaC‐ e minal
globula domainwi hGTac i i y.Inaddi ion, hes uc u eo heenzymeDUF1792 e ealedano el
olddesigna edasGT‐D ype[47]andde ined amilyGT101.Membe so heGT51 amilyalsoha e
adis inc s uc u ede inedaslysozyme‐ ype[48,49],and he ecen lypublisheds uc u eo TagA,a
membe o heGT26 amily,sugges s hede ini iono ano el old e medGT‐E[50].Acommon
ea u e oundinmanymembe so heGT‐AandGT‐Csupe amiliesisaDxDmo i in ol edin
binding odi alen me alionandca alysis.Howe e , heoccu enceo hismo i isno enough o
p edic apo en ialGT unc ionsincemanyGTsdono possessi and heDxDmo i is oundinmo e
hanahal o alldesc ibedp o eins[32].Finally,gi en hemodula na u eo ca bohyd a e‐ac i e
enzymes,anumbe o GTscon ainnonca aly icdomainspo en iallyin ol edinsubs a e
ecogni iono p o ein–p o einin e ac ion,andsomepolypep idescon ain woGTmodules
belonging o hesameo di e en amilies.
Figu e3.Glycosyl ans e ase olds.(a)Diag amo heGT‐A oldp o einSpsA omBacillussub ilis,
belonging o amilyGT2(PDBID:1QG8)[51];(b)diag amo heGT‐B old‐ ypep o einG B om
Amycolap osiso ien alis,belonging o amilyGT1(PDBID:1IIR)[52];(c)diag amo heGT‐C old
p o einPglB omCampylobac e la i,belonging o amilyGT66(PDBID:3RCE)[46].D awingsc ea ed
wi hNGL[53].
Table1showsaclassi ica iono GT amiliesbasedon eac ionmechanismsand old ypes.
Mic oo ganisms2020,8,3575o 23
Table1.Classi ica iono glycosyl ans e ase amilies.
Reac ionMechanism
In e ingRe ainingUnknown
Fold ype
GT‐A21
,
7,12,13,14,16,21,29,31,42,43,
82,84,109
6,8,15,24,27,
34,44,55,62,
64,78,81,88
GT‐B1,9,10,18,19,23,28,30,33,38,41,
52,63,65,68,70,80,90,104
3,4,5,20,35,
52,72,99,107
GT‐C22,39,50,53,57,58,59,66,83,85,87
O he s26(GT‐E),51(lysozyme‐ ype), 101(GT‐D)
Unknown
11,17,25,37,40,47,48,49,54,56,
61,67,73,74,75,76,92,94,97,98,
100,102,103,105,106,108
32,45,60,69,
71,77,79,89,
93,95,96
91,110
1Numbe sco espond o heGT amilynumbe sassignedin heca bohyd a eac i eenzymes
(CAZy)da abase.
3.Glycosyla ioninBac e ialPa hogenesis
Asmen ionedin hein oduc ion,e ec o s ompa hogenicbac e iao enexhibi speci ic
enzyma icac i i yagains hos cell a ge saspa o i sin ec ions a egy.P o einglycosyla ion, he
mos commonpos ‐ ansla ionalmodi ica ion,hasbeen adi ionally hough obe es ic ed o
euka yo ico ganisms.Howe e ,in helas yea s,manyexampleso bac e ial i ulence ac o sand
oxinsexhibi ingGTac i i yha ebeencha ac e ized[54].Bac e ialglycosyla ionisb oadlylinked
obac e ialpa hogenesis[55].I ul ills womain unc ionsdu ingin ec ion: i s ly,p o ein
glycosyla ionenablesbac e ialadhesion ohos cellsand,secondly,leads omodi ica iono speci ic
hos a ge swi h heconsequen manipula iono hos cellula p ocessesby hepa hogen o hei own
bene i .
Bac e ialGTspe o m wo ypeso p o einmodi ica ions:N‐linkedglycosyla iono O‐linked
glycosyla ion[29].Whe easN‐GTsconjuga eglycans osidechainamideni ogeno anaspa agine
inanAsn‐X‐Se /Th consensussequence,O‐glycosyla ionhappenson hehyd oxylg oupo ase ine
o h eonine esidue.Bo hN‐linkedandO‐linkedglycosyla ionpa hwaysmaymodi ymul iple
p o eins.In e es ingly, he ea eexampleso pa hogenicbac e ia,likeC. oden ium,pe o mingN‐
andO‐glycosyla ion ha a ebo hc i ically equi ed o coloniza iono hegas oin es inal ac in
in ec edmice[54].
In hissec ionwep o ide ep esen a i eexampleso wellcha ac e izedbac e ialGTs,a ending
o hei speci icbiological oledu ingin ec ionand he ypeo modi ica ion heype o m.
3.1.Glycosyla iono Adhesins
Oneessen ials ep oini ia ein ec ionisbac e ialadhesion o hehos epi helium.This i s s ep
dependssome imesonglycosyla iono bac e ialadhesins.Someexamplesa edesc ibedbelow.
Awell‐knownexampleis hehigh‐molecula ‐weigh (HMW)sys emo Haemophilusin luenza.
HMW1/HMW2a e woadhesins ha a eglycosyla eda hecy oplasmbyGTsHMW1Cand
HMW2C, espec i ely[56,57].Then, heya e anspo ed o hebac e ialsu aceandmedia e
adhe ence o espi a o yepi helialcells[57].Glucoseandgalac osea eadded ospeci ic
aspa agine esiduesin heeuka yo ic‐likeAsn‐X‐Se /Th consensus[58].
Pgl( omP o einglycosyla ion)sys eminCampylobac e jejuniisano he exampleo a
glycosyla edadhesin ha hasbeenconside edap o o ype o he ele anceo bac e ial
Mic oo ganisms2020,8,3576o 23
glycosyla ioninbac e ial–hos in e ac ion[55].I isanN‐linkedp o einglycosyla ionsys em
composedo se e alp o eins,including a iousGTs ha modi yC.jejunip o einsleading o
bac e ial–hos celladhesionandin asiono hos epi helium[59].Dis up iono hePglpa hway
esul sin educ iono humanepi helialcellsadhesionanddec eases heabili y ocolonize
mouseandchickenin i o[59–61].Modi ica ionca alyzedby hePglsys emconsis so he
addi iono ahep asaccha ide oaspa agine esidueswi hin heeuka yo ic‐likeAsn‐X‐Se /Th
glycosyla ionconsensus.Theoligosaccha ideisassembledon hecy oplasmicsideo heinne
memb ane.Then,i is ansloca edbyanABC‐ anspo e (PglK)[62].Oncein hepe iplasmic
space,PglB,anoligo‐saccha yl ans e ase, ans e s hehep asaccha ide oaspa agine esidues
o a ge ligands[63,64].
Inaddi ion oN‐glycosyla ion‐ ela edmechanisms oimp o ebac e ialadhesion,o he sys ems
basedonO‐glycosyla ionha ebeencha ac e ized.Oneexampleis heeme gingbac e ial
au o anspo e hep osyl ans e ase(BAHT) amily oundinse e alG am‐nega i ebac e ia
[65].Au o anspo e swhichbelong o heT5SS amilyha eamodula composi ionwi hanN‐
e minalpassenge domainandaC‐ e minalβ‐ba eldomain ha d i es hepassenge ac oss
heou e memb ane.Thepassenge domainmaybehep osyla edbyaBAHTmembe on
nume ousse ine esidues.Thismodi ica ionoccu sbe o e ansloca iono hep o einac oss he
inne memb aneandis equi ed o bac e ialadhesion o hehos .Twowell‐cha ac e ized
BAHTmembe a eAAH(au o anspo e adhesinhep osyl ans e ase), omdi uselyadhe ing
E.coliisola e2787,andTibC omen e o oxigenicE.colis ainH10407[65,66].Inaddi ion o
pa hogenicE.coli,BAHTmembe sha ebeeniden i iedino he bac e ia,includingCi obac e ,
Shigella,Salmonella,andBu kholde ia[65].Fu he s udiesa enecessa y o ullycha ac e ize hese
in e es ingbac e ialenzymes.
Pos ‐ ansla ionalmodi ica iono bac e ialp o eins oenhancebac e ialadhesion o hehos is
no es ic ed oG am‐nega i ebac e ia.Awell‐knownexampleo modi iedbac e ialp o eins
inG am‐posi i ebac e iaa e heO‐glycosyla edse ine‐ ich epea p o eins(SRRPs)[67].These
la geglycop o eins,uniqueinG am‐posi i ebac e ia,a ec ucial o bio ilm o ma ionand,
mo eimpo an ly,hos celladhesion[68].Thebes ‐cha ac e izedSRRPisFap1 om
S ep ococcuspa asanguinis.Glycosyla iono Fap1 elieson heac i i yo a leas sixdi e en
GTs,al hough hespeci ic unc ionandglycan ans e ed emainsunclea [69].This amilyo
glycop o einsishighlyconse edamongs ep ococcalands aphylococcalspecies[67], hus,
cha ac e iza iono SRRPsGTsandunde s andingo hei biological olea ekey oiden i ynew
he apeu icd ug a ge sino de o ackle ele an G am‐posi i epa hogens.
3.2.Glycosyla iono Flagellins
Glycosyla iono lagellinisanimpo an componen o nume ous lagella sys emsinA chaea
andBac e ia,playinganimpo an oleinassemblyand i ulence[70],since hiso ganelle,in
addi ion ocon e ingmo ili y,canplaya oleine e ys epo hein ec ioncycle[71].FlagellaO‐
glycosyla ionhasbeendemons a edinmanypola lagellins omG am‐nega i e[72]andG am‐
posi i ebac e ia[73–80],andalsoinalimi ednumbe o la e al lagellins[72,81,82].Bac e iacan
glycosyla e lagellina a a yingnumbe o accep o si es, omasinglesi einBu kholde iaspp.o
Lis e iamonocy ogenes omul iplesi esinC.jejunio Selenomonasspu igena[80,83–85].Mo eo e ,
whe eassomebac e iauseasinglemonosaccha ide,o he sshows ain‐ o‐s ainglycan
he e ogene i y[72].Selec edexamplesa edesc ibedbelow.
InAe omonasca iaeSch3N, hepola lagellins,FlaAandFlaB,a eglycosyla edwi h
pseudoaminicacidglycansand hisglycosyla ionis equi ed o lagella assembly.Genes
in ol edinglycosyla iona emappedin heO‐an igenbiosyn he icclus e [86,87].InAe omonas
hyd ophilaAH‐3,la e al lagellinismodi iedwi hade i a i eo pseudaminicacid,whe eas
pola lagellaa eglycosyla edwi hahe e ogeneousglycan[88].
C.jejuniFlaAisglycosyla eda up o19si es ha con ibu e o he lagellumse ospeci ici y.FlaB
isalsoglycosyla ed,bu henumbe o si es emains obees ablished.Thep edominan O‐
glycansa ede i a i eso pseudoaminicacidandlegionaminicacid.ThegenesencodingGTs
Mic oo ganisms2020,8,3577o 23
in ol edin lagellinglycosyla iona eloca edadjacen o he lagellins uc u algenes, laAand
laB[85,89,90].
InHelicobac e pylo i,bo h heFlaAandFlaBs uc u alp o einsa eglycosyla edwi h
pseudomainicacida se enand ensi es, espec i ely.Biosyn hesiso pseudaminicacidhas
beenex ensi elys udiedinH.pylo iandC.jejuniandin ol essixconsecu i eenzyma ics eps
be o ebeing ans e edon o lagellins iaO‐linkedglycosyla ion[91,92].
TheGT ans e ingpseudaminicacidon o lagellinhasbeens udiedinMagne ospi illum
magne icumAMB‐1[93].ThisGT,knownasMa ,displayssigni ican sequenceiden i ywi h
p o eins omo he G am‐nega i ebac e ia,includingMa 1 omA.ca iaeandPseE omC.
jejuni, ha ha ebeenshown o ans e pseudaminicacidon o lagellinsin heseo ganisms
[94,95].Thes uc u eo M.magne icumMa displaysamodi iedGT‐A opologyas oundin
CAZy amiliesGT29andGT42.In ac , hecloses s uc u alhomologueisC.jejuni
sialyl ans e aseCs ‐II(PDB1RO7),belonging o amilyGT42[93].
Glycosyl a iono Clos idiumdi icile lagellinisessen ial o mo ili y.Two ypeso modi ica ion
ha ebeende inedas ypeAandB.TypeAmodi ica ionin ol esanO‐linkedN‐
ace ylglucosamine(GlcNAc)linked oame hyla ed h eonine iaaphosphodies e bond.Th ee
GTsa ein ol edin ypeBmodi ica ion:GT1andGT2a e esponsible o hesequen ialaddi ion
o aGlcNAcand wo hamnoses, espec i ely,andGT3isassocia edwi h heinco po a iono
asul ona edpep idyl‐amidosuga moie y[74].
3.3.Modi ica iono Hos CellTa ge sbyBac e ialGTs
Inaddi ion obac e ialGTs ha glycosyla e hei ownp o eins,we indano he in e es ing
g oupo bac e ialp o eins ha modi yhos cellp o eins,manipula ing hecellphysiology o
coun e ac hehos de ense esponse.Thela geclos idial oxinsTcdA/TcdB, heLegionellacy o oxic
glycosyl ans e ase amily(Lg ),andN‐GTs om heNleB/SseK amilya eincludedin hisg oup
[54].
La geclos idialglycosyla ing oxins:pa hogenesiso Clos idiumdependson heac i i yo wo
simila oxins,TcdAandTcdB, ha exhibi GTac i i yin hei N‐ e minaldomains[96,97].Bo h
oxinspe o mO‐glycosyla iono smallGTPaseso heRho amily,inhibi ing he egula o y
unc ionso hesep o eins[98].Thismodi ica ionoccu son hesidechainhyd oxylg oupo a
h eonine esidue,whichisspeci ic o each a ge edRhoGTPase[99].Ano he exampleo his
amilyo oxins ecen lyiden i iedisPaTox omen omopa hogenicPho o habdusasymbio ica
[100].
LegionellapneumophilaLg amily:L.pneumophilais hecausa i eagen o legionellosis,ase e e
lungdisease.This acul a i ein acellula pa hogenusesaT4SS oinjec mo e han300e ec o s
in o hehos cell[101].Among hem,L.pneumophilasec e esse e alGTs(Lg 1‐3) ha pe o m
speci icglycosyla iono ase ine esidue(Se 53)in heeuka yo icelonga ion ac o 1A,ala ge
GTPaseandacomponen o heelonga ioncomplexinp o einsyn hesis.Thismodi ica ion
esul sininhibi iono p o einsyn hesisandsubsequen lycauses hedea ho in ec edcells
[102,103].In e es ingly,Lg 1sha ehighs uc u alhomologywi h heclos idial oxinTcdB.
Bo hGTsa emembe so heclanIIIo e ainingenzymeswi h heGT‐A old[103–105].
NleB/SseK amily:we e e o his amilyo T3SSe ec o sin henex sec ion.
4.Glycosyl ans e aseso heNleBFamily
4.1.Membe so heFamily
T3SSe ec o s ha ca alyze he ans e o GlcNAc oa ginineso hos p o einsha ebeen
s udiedinC. oden ium,EHEC,EPEC,andS.en e ica(Table2).
Mic oo ganisms2020,8,3578o 23
Table2.NleB/SseKglycosyl ans e ases.
O ganism.
Re e ence
S ainE ec o NameP o einSize
(aa)GenomicCon ex Re e ences
C. oden iumICC168NleB329GenomicislandGI4[106,107]
En e ohemo hagic
E.coli(EHEC)
O157:H7
EDL933
NleB1329O‐island122/SpLE3
[106,108]
NleB2326O‐island36/PhageCP‐
933K/Sp3
En e opa hogenicE.
coli(EPEC)O127:H6E2348/69
NleB1329In eg a i eelemen IE6
[109,110]
NleB2326PhagePP4
S.en e icase o a
Typhimu ium14028
SseK1336
[111–113]
SseK2348
SseK3335PhageST64B
NleBwasiden i iedinC. oden ium oge he wi ho he po en ial ypeIIIe ec o sencoded
ou side heLEE.Theywe edesigna edNleA,NleB,NleC,NleD,NleE,NleF,andNleG o non‐LEE‐
encodede ec o s[106].Twohomologso NleBa eencodedin hegenomeso EHECandEPEC:
NleB1andNleB2[106,108,109].NleB1is89%iden ical oNleB omC. oden ium,and he eisa
di e enceinse enaminoacidsbe ween heEHECandEPEC e sions.NleB2isiden icalinbo hE.
colipa ho ypesbu isonly60%iden ical oC. oden iumNleB,al houghano hologo nleB2isp esen
in hegenomeo C. oden iumasapseudogene[107].In e es ingly,nleB2isanon‐neu ale ol ing
gene,p obablydue oposi i eselec ion,sugges ing ha hisgeneiss illin hep ocesso op imizing
i s unc ion[114].S.en e icas ainsencode h eehomologso NleB:SseK1,SseK2,andSseK3
[111,112].Al hough hegenesencoding hesee ec o sa eno loca edin hepa hogenici yislands
whe e hecogna eT3SSa eencoded,allo hemha ee idenceo ho izon al ans e andsomea e
associa edwi ho he pa hogenici yislandso p ophages(Table2).In e es ingly,whe eassseK1and
sseK2a ep esen inmos a ailableSalmonellagenomesequences, hephage‐encodedSseK3e ec o
hasalimi eddis ibu ion[111].ABLASTsea choncomple egenomesa ailablea heNa ional
Cen e o Bio echnologyIn o ma ion(NCBI) e eals ha p o einsiden icalo e ysimila oNleB1
o NleB2a eencodedindi e en s ainso heeme gingA/Epa hogenEsche ichiaalbe ii[115],and
signi ican lysimila p o einsa e oundinEsche ichiama mo ae[116]andYe siniahibe nica[117].
Pe cen ageso iden i ybe ween ep esen a i eNleB/SseKp o einsa eshowninTable3,anda
phylogene icanalysisisshowninFigu e4.
Table3.Pe cen iden i yda a o NleB/SseKp o einsp o idedbyClus alW.
NleBC.
oden ium
NleB1
EPEC
NleB1
EHEC
NleBE.
albe ii
NleBE.
ma mo aeNleB2SseK1SseK2SseK3
NleBC. oden ium
NleB1EPEC88.75
NleB1EHEC89.0697.87
NleB1E.albe ii88.4597.5799.09
NleBE.ma mo ae71.4271.7371.7371.43
NleB2EPEC/EHEC59.8261.0461.3560.4360.43
SseK1S.en e ica57.4558.0559.5758.9758.9753.68
SseK2S.en e ica52.5852.2853.1952.5851.0646.9355.36
Mic oo ganisms2020,8,3579o 23
SseK3S.en e ica51.9853.1953.5052.8954.1047.5554.9375.22
NleBY.hibe nica32.5232.8334.0434.0434.0433.1335.1233.1433.43
Figu e4.Phylogene icanalysiso NleB/SseKp o eins.Alignmen andphylogene ic econs uc ions
we epe o medusing he unc ion“build”o ETE3 3.1.1[118]asimplemen edon heGenomeNe
(h ps://www.genome.jp/ ools/e e/).The eewascons uc edusingFas T ee 2.1.8wi hde aul
pa ame e s[119].Valuesa nodesa eSH‐likelocalsuppo .
4.2.Exp ession,T ansloca ion,andSubcellula Localiza ion
E ec o so T3SSsa eexpec ed obeexp essedincoo dina ionwi h hesyn hesiso hei
cogna esec e ionappa a us.Thisis hecase o e ec o so heLEE,SPI1o SPI2sys ems ha a e
encodedin heislands,bu heissueisno soob ious o e ec o sencodedou side heislands,
including hemembe so heNleB/SseK amily.
InA/Eo ganisms,Le is hemain ansc ip ional egula o o LEE.I isencodedin heisland
andi sle eliscon olledbyo he ansc ip ional egula o s ha espond odi e en en i onmen al
s imuli,includinghos ho mones,mic obio a‐libe a edsuga sandme aboli es,molecula oxygena
hegu epi helium,andcon ac o bac e iawi hhos epi helialcells[120].Exp essionisunde ec able
whenbac e iaa eg ownin ichlabo a o ymedia,bu apidexp essionandsec e iono p o eins o
hesupe na an isobse edupon ans e oMEM‐HEPESmedium,whichisassocia edwi h he
he e ogeneousexp essiono heEspADB ansloconappa a us[121].Se e alnlegenes,including
nleB,a e ansc ibedinEHECunde hesesec e ion‐pe missi econdi ions,al houghinduc iono
nleBexp essionwassligh ( wo old)andwasno coo dina edwi h hesyn hesiso EspA ilamen s
a hesingle‐cellle el[122].Sec e iono NleB(NleB1inEPEC)by heLEE‐encodedT3SShasbeen
demons a edinC. oden iumandEPEC[106,110].T ans ec ionwi hGFP‐ usionso ansloca iono
TEM‐1β‐lac amase usions[123] omEPECin oHeLacells e ealsadi usecy osoliclocaliza iono
NleB1[110,124].The egula o y egiono EPECnleB2con ainsamo i conse edamongasubse o
genesencodinge ec o p o einsinA/Epa hogens ha wasnamedNRIR(nle egula o yin e ed
Mic oo ganisms2020,8,35716o 23
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