The Proteasomal System in Aging and Disease

425 Pages·2012·8.433 MB·1-422\425

by  Tilman Grune (Eds.)

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Contributors
Numbersinparenthesesindicatethepagesonwhichtheauthors’contributionsbegin.
Martin A. Baraibar, Laboratoire de Biologie Cellulaire du Vieillissement,
UR4-IFR83, Universite´ Pierre et Marie Curie–Paris 6, 4 place Jussieu,
ParisCedex05,France(249)
Betul Catalgol, Department of Biochemistry, Faculty of Medicine, Genetic
andMetabolicDiseasesResearchCenter(GEMHAM), MarmaraUniversity,
Haydarpasa,Istanbul,Turkey(277,397)
Niki Chondrogianni, National Hellenic Research Foundation, Institute of
Biology,MedicinalChemistryandBiotechnology,Athens,Greece(41)
Boris Cvek, Department of Cell Biology & Genetics, Palacky University,
Olomouc,CzechRepublic(161)
Kelvin J. A. Davies, Ethel Percy Andrus Gerontology Center of the Davis
SchoolofGerontologyandDivisionofMolecular&ComputationalBiology,
Department of Biological Sciences, Dornsife College of Letters, Arts &
Sciences: The University of Southern California, Los Angeles, California,
USA(227)
Deborah A. Ferrington, Department of Ophthalmology, University of
Minnesota,Minneapolis,Minnesota,USA(75)
Bertrand Friguet, Laboratoire de Biologie Cellulaire du Vieillissement,
UR4-IFR83, Universite´ Pierre et Marie Curie–Paris 6, 4 place Jussieu,
ParisCedex05,France(249)
Efstathios S. Gonos, National Hellenic Research Foundation, Institute of
Biology,MedicinalChemistryandBiotechnology,Athens,Greece(41)
DaleS.Gregerson,DepartmentofOphthalmology,UniversityofMinnesota,
Minneapolis,Minnesota,USA(75)
Tilman Grune, Institute of Nutrition, Friedrich Schiller University, Jena,
Germany,(1,113,397)
Joerg Herrmann, Department of Internal Medicine, Division of Cardiovas-
cularDiseases,MayoClinic,Rochester,Minnesota,USA(295)
Tobias Jung, Institute of Nutrition, Friedrich Schiller University, Jena,
Germany(1)
Marc Ka¨stle, Institute of Nutrition, Friedrich Schiller University, Jena,
Germany(113)
AmirLerman,DepartmentofInternalMedicine,DivisionofCardiovascular
Diseases,MayoClinic,Rochester,Minnesota,USA(295)
ix
x contributors
CamPatterson,DepartmentofMedicine;DepartmentofPharmacology,and
Department of Cell and Developmental Biology, The McAllister Heart
Institute, University of North Carolina Chapel Hill, North Carolina, USA
(295)
AndrewM.Pickering,EthelPercyAndrusGerontologyCenteroftheDavis
SchoolofGerontologyandDivisionofMolecular&ComputationalBiology,
Department of Biological Sciences, Dornsife College of Letters, Arts &
Sciences: The University of Southern California, Los Angeles, California,
USA(227)
SaulR.Powell,CenterforHeartandLungResearch,TheFeinsteinInstitute
forMedicalResearch,Manhasset,NewYork,USA(295)
Fu Shang, Laboratory for Nutrition and Vision Research, USDA Human
NutritionResearchCenteronAging,Boston,Massachusetts,USA(347)
Allen Taylor, Laboratory for Nutrition and Vision Research, USDA Human
NutritionResearchCenteronAging,Boston,Massachusetts,USA(347)
Xuejun Wang, Protein Quality Control and Degradation Research Center,
Division of Basic Biomedical Sciences, Sanford School of Medicine,
UniversityofSouthDakota,Vermillion,SouthDakota,USA(295)
Preface
The proteasomes, together with the proteasome-associated proteins and
cellular systems, are among the most complex cellular structures. Literally,
thereisnocellularprocesswithoutinvolvementofproteins,whichneedtobe
degraded in a controlled manner or removed if they are damaged and this
functionislargelytakenoverbytheproteasome.Thisleadingroleofthepro-
teasomeamongtheintracellularproteasesleads,therefore,toaninvolvement
oftheproteasomalsysteminalmostallcellularprocesses.
Duringevolution,severalsystemsdevelopedwiththeaimtomaintainthe
integrityofthecellularproteinpool.Theideathatproteinsarenotstablewithin
the body but undergo a permanent turnover was first raised by Scho¨nheimer
andcolleaguesinthelate1930s.1However,howthesepathwayswererealized
remainedunknownuntilChristiandeDuvediscoveredintheearly1950sthe
lysosomes,leadingtothediscoveryoftheirenzymaticactivities, includingthe
proteolytic enzymes.2 It was accepted for some time that lysosomes were
responsibleforthedegradationofmostcellularstructures,includingproteins.
The proteasome was discovered as a structure in 1968/1969 by Harris et al.3
Ittooksometimetoassociatethisparticlewiththeprocessofproteindegradation
andonlythedescriptionoftheubiquitinationprocessledtothediscoveryofthe
realfunctionsoftheproteasome.Oneofthekeyarticleswaspublishedin1978by
Ciechanover,Hod,andHershkodescribingtheinvolvementofseveralfractions
of reticulate lysate in the ATP-dependent degradation of globin.4 In 2004, this
pioneeringresearchwasacknowledgedwithawardingtheNobelPrizeinchem-
istryforCiechanover,Hershko,andRose.
Eversincethen,theresearchontheproteasomebecamewiderandwider
andledtothediscoveryoftheroleoftheproteasomalsysteminthepathophys-
iologyofseveralhumandiseasesandinthephysiologyoftheagingprocessitself.
This volume focuses on some major roles of the proteasome in human
healthanddisease.Thevolumeisdividedintotwoparts:thefirstpart(Chap-
ters 1–5) describes the current knowledge of the structure, function, and
regulation of the proteasomal system, whereas the second part (Chapters
6–11)describestheroleoftheproteasomeinaginganddisease.
The structure of the proteasome is described in a chapter by Jung and
Grune,referringtotoday’sknowledgeonthestructureofthe20Sproteasome
andofsomeoftheproteasomalregulators.ThenextchapterbyChondrogianni
andGonosfocusesonthefunctionofthissystemwithspecialattentiontothe
xi
xii preface
ubiquitin system. In the next chapter, Ferrington and Gregerson describe a
specialformoftheproteasomalsystem—theimmunoproteasome.Thisprotea-
somal form was found to be induced by immunostimulatory cytokines. How-
ever,today’sunderstandingattributes functionsbeyond theimmuneresponse
to the immunoproteasome. A relatively new field is the understanding of the
interaction of the proteasomal system with chaperons and the interactions of
bothsystemsasaresponsetotheaccumulationofunfoldedproteinsaswellin
theERasinthecytosol.ThisisreviewedinthechapterbyKa¨stleandGrune.
Thelastchapterofthefirstpartofthevolume,writtenbyCvek,describesthe
wealthofproteasomalinhibitorsknowntoday.
Thesecondpartofthevolumedescribestheroleoftheproteasomalsystem
in physiology and pathophysiology of disease and aging. One of the first
functionsattributedtotheproteasomealreadyinthemid-1980sistheselective
degradationofoxidativelymodifiedproteins.5Eversincethenourunderstand-
ing of this process is becoming better, as reviewed by Pickering and Davies.
However,theproteasomalsystemitselfisalsoaffectedbyoxidativestressand
aging.Theroleoftheincreasinglyfailingproteasomalfunctionduringagingis
describedbyBaraibarandFriguet.Moreover,theproteasomalfunctionisalso
affected by diseases. This refers to the proteasomal malfunction in cardiovas-
cular diseases, neurodegeneration, and eye diseases, as reviewed by Powell
et al., Shang/Taylor, and Catalgol/Grune. Special attention was given to the
possibilitiesoftreatmentofcancercellswithproteasomalinhibitors,asshown
inthechapterofCatalgol.
As you will see, by studying this volume, one can hardly overestimate the
importance of the UPS for normal cellular metabolism. By realizing that this
systemisconservedduringevolutionfromarchaebacteriathroughmammals,its
importanceisfurtherunderlined.Duringitsevolution,componentsofthepro-
teasomal system diverged in order to meet the ever more challenging tasks in
morecomplex organisms. The proteasomal system interacts with an increasing
numberofothercellularsystems.Itisexpectedthattheresearchontheprotea-
somalsystemwilldiscovermorefunctionsinnearfuture.Furthermore,asalready
demonstratedbytheusageofproteasomalinhibitorsincancer,moretherapeutic
approachesorstrategiesareexpectedtobedevelopedinthefuture—eitherfor
theproteasomedirectlyorfortheproteasome–ubiquitinsystem.
TilmanGrune
VolumeEditor
References
1. Scho¨nheimerR,RittenbergD,FosterGL,KestonAS,RatnerS.Theapplicationofthenitrogen
isotopeN15forthestudyofproteinmetabolism.Science1938;88:599–600.
preface xiii
2. de Duve C, Gianetto R, Appelmans F, Wattiaux R. Enzymic content of the mitochondria
fraction.Nature1953;172:1143–4.
3. Harris JR. The isolation and purification of a macromolecular protein component from the
humanerythrocyteghost.BiochimBiophysActa1969;188:31–42.
4. CiechanoverA,HodY,HershkoA.Aheat-stablepolypeptidecomponentonanATP-dependent
proteolyticsystemfromreticulocytes.BiochemBiophysResCommun1978;81:1100–5.
5. DaviesKJ.Freeradicalsandproteindegradationinhumanredbloodcells.ProgClinBiolRes
1985;195:15–27.
Structure of the Proteasome
TobiasJungandTilmanGrune
InstituteofNutrition,FriedrichSchiller
University,Jena,Germany
I.Introduction.................................................................................. 1
II.The20SProteasome........................................................................ 2
A. TheProteasomala-Subunits......................................................... 7
B. TheProteasomalb-Subunits......................................................... 10
C. IntracellularAssemblyofthe20SProteasome................................... 12
D. Modelingofthe20SProteasomalProteolysis.................................... 15
III.Regulationofthe20SProteasome....................................................... 15
A. The19SRegulator...................................................................... 16
B. TheImmunoproteasome.............................................................. 16
C. TheThymus-SpecificProteasome(Thymoproteasome)........................ 19
D. The11SRegulator...................................................................... 20
E. TheHybridProteasome(PA28–20S–PA700)..................................... 21
F. ThePA200RegulatorProtein........................................................ 23
IV.Conclusion.................................................................................... 25
References.................................................................................... 26
The ubiquitin-proteasomal system is an essential element of the protein
quality control machinery in cells. The central part of this system is the 20S
proteasome. The proteasome is a barrel-shaped multienzyme complex, con-
tainingseveralactivecentershiddenattheinnersurfaceofthehollowcylinder.
So,theregulationofthesubstrateentrytowardtheinnerproteasomalsurface
isakeycontrolmechanismoftheactivityofthisprotease.
This chapter outlines the knowledge on the structure of the subunits of
the20Sproteasome,thebindingandstructureofsomeproteasomalregulators
andinducibleproteasomalsubunits.Therefore,thischapterimpartstheknowl-
edgeonproteasomalstructurewhichisrequiredfortheunderstandingofthe
followingchapters.
I. Introduction
Inordertomaintainthefunctionalityandtheviabilityofacell,mostofthe
cellular proteins are subjected to a highly regulated turnover. To realize this,
proteinsthataremisfolded,(oxidatively)damaged,ornolongerrequired,have
to be recognized and removed.1–4 Removal of proteins is usually realized via
proteolyticdegradation.Themostimportantproteolyticintracellularsystemof
thecytosolistheproteasomalsystem,anevolutionarilyveryoldanddistributed
machinerythatwasfoundtobepresenteveninmanyoftheoldestbacteria,as
ProgressinMolecularBiology Copyright2012,ElsevierInc.
andTranslationalScience,Vol.109 1 Allrightsreserved.
DOI:10.1016/B978-0-12-397863-9.00001-8 1877-1173/12$35.00
2 JUNG AND GRUNE
wellasinplantsandanimals.Thecentralpartoftheproteasomalsystemisthe
20S ‘‘core’’ proteasome, a large multisubunit and multicatalytic protease, as
wellasseveraldifferentregulatorsthatcanchangetheactivityofthespecificity
ofthe‘‘core’’particle.
Inthefollowingsections,wedescribethestructureandfunctionofthe20S
proteasome and its regulators. For a better differentiation between the varia-
tions of the ‘‘proteasome,’’ the 20S ‘‘core’’ particle is always referred to as
‘‘proteasome,’’andtheotherforms,accordingtotheregulatorsthatareattached
tothat‘‘core.’’
II. The 20S Proteasome
The 20S proteasome represents the catalytic part of the proteasomal
system, a highly regulated group of proteins that perform degradation of
damaged or misfolded proteins, regulation of their life spans,1–6 and ‘‘quality
control’’ofnewlysynthesizedproteins7–12thatareinvolvedinregulationofthe
cell cycle,5 gene expression,13–17 immune responses,18–23 responses to (oxida-
tive) stress,24–28 and carcinogenesis.29–31 Furthermore, the nuclear protein is
involved in the maintenance of chromatin and influences DNA repair.32–34
So an evermore increasing spectrum of cellular functions are related to the
proteasomalsystem.
Theterm‘‘20S’’resultsfromthesedimentationconstantoftheproteasome
‘‘core’’ particle.35 The mammalian form of this particle is of a cylindrical
structure of about 100(cid:1)160A˚ that contains four homologous rings (two
alpha (a-) and two beta (b-)rings, arranged in the sequence a-b-b-a), which
are built of seven different subunits each. The three-dimensional structure
ofthelargeproteaseofseveralorganismshasbeeninvestigatedextensivelyvia
X-raycrystallography.36–41
Two basic forms of the proteasome are known: the ancestral one that is
foundinArchaeabacterialikeThermoplasmaacidophilumandtheevolution-
arilyhigherformofyeast,plants,andanimals.
As the evolutionary higher form, the ancestral proteasome contains four
heptameric rings, arranged in the common a-b-b-a sequence, but in this
ancestral proteasome each ring contains seven equal subunits, so only one
a- and b-subunitarepresent(seeFig.1).Itisobviousthatfromthesesimple
forms of the proteasome a more complex one evolved via the divergence of
the single subunits into several homologous ones. So the evolutionary higher
form of the 20S proteasome contains 14 different subunits overall (a –a and
1 7
b –b ), showing molecular masses between 20 and 30kDa (see Table I),
1 7
summarizing to a molecular weight of some 700kDa. While the catalytic
centers are located in the inner b-rings, the outer a-rings of the proteasome
STRUCTUREOFTHEPROTEASOME 3
Side view Perspectiveview Top view
b
a-ring
a
a
b-ring
b
b-ring
a-ring
5 nm
FIG.1. Thestructureofthearchaea20SproteasomefromThermoplasmaacidophilum.This
figure shows a basic model of the archaea proteasomal structure. As shown on the left, the
proteasomecontains four homologousringsin thesequencea-b-b-a. Eachringcontainsseven
identicalsubunits:thea-ringonlya-,theb-ringonlyb-subunits,asshowninthecentralimage.The
rightpanelshowsthearrangementofthea-subunitsinaverticalviewontoana-ring.
areresponsiblefortheregulationofsubstrateentrancetotheinnerproteolytic
chamber,aswellasforrecognitionandbindingofthesubstratesthemselves.So
the a-subunits are able to change both the activity and specificity of the
proteasome. The proteolytic centers found in the inner rings are encoded by
threedifferentb-subunits(b ,b ,andb ).Thus,duetothesymmetricarrange-
1 2 5
mentofthedifferentrings,theinnerchambercontains6differentproteolytic
centers,protectedinsidetheproteasomeintheevolutionaryhigherformofthe
proteasome, but 14 in the ancestral one. The inside of the proteasome is
subdivided into two ‘‘ante chambers’’ (between the a- and b-rings) and one
single‘‘mainchamber,’’foundbetweenthetwob-rings(seeFig.2).The‘‘main
chamber’’isalsothelocationofthecatalyticcenters.
As the proteasome is today referred to as a proteolytic system, several
regulators are binding to the core proteasome, modulating the proteasomal
activity.Today,asetofseveraldifferentproteasomalregulatorsareknown,all
binding to the a-subunits of the outer proteasomal rings. The 11S regulator
particle, in most organisms termed ‘‘PA28’’ or ‘‘REG,’’ is formed of three
different subunits (PA28a, PA28b, and PA28g arranged in several diverse
combinations). In Trypanosoma brucei, this ATP-independent regulator is
called‘‘PA26.’’AnotherimportantregulatoristheATP-dependent ‘‘19S,’’also
knownas‘‘PA700’’regulator;itsanalogueinarchaeaistermed‘‘PAN.’’Several
otherregulatorsareknown,includingthenuclearregulator‘‘PA200,’’whichis
known in three different isoforms (PA200i, PA200ii, and PA200iii) and
4 JUNG AND GRUNE
TABLEI
HERE,THEMOLECULARMASSES(AFTERPOSTTRANSCRIPTIONALPROCESSING,ASFOUNDINTHE
ASSEMBLEDWHOLE20S‘‘CORE’’PROTEASOME)OFTHEPROTEASOMALSUBUNITSFROMBOTHHUMAN
ANDYEASTPROTEASOMEARELISTED,ASWELLASTHESUBUNITSOFTWOPROTEASOMALREGULATORCAPS
(11SAND19S)
20S‘‘core’’proteasome
Systematic S.cerevisiae Homosapiens Mass[kDa] Literature
a C7/Prs2 HsPROS27/HsIota 27.5 42
1
a Y7 HsC3 25.9 43,44
2
a Y13 HsC9 29.5 45,46
3
a Pre6 HsC6/XAPC7 27.9 47,48
4
a Pup2 HsZeta 26.4 49–51
5
a Pre5 HsC2/HsPROS30 30.2 52
6
a C1/Prs1 HsC8 28.4 53–56
7
b Pre3 HsDelta/Y 25.3(21.9) 57–59
1
b – Lmp2 23.2(20.9) 60–63
1i
b Pup1 Z 20.0(24.5) 64–66
2
b – Mecl1 28.9(23.8) 67,68
2i
b Pup3 HsC10-II 22.9 69,70
3
b C11/Pre1 HsC7-I 22.8 69,71
4
b Pre2 X/MB1 N/A(22.4) 71
5
b – Lmp7 30.4(21.2) 67,72–74
5i
b C5/Prs3 HsC5 26.5(23.3) 75,76
6
b Pre4 HsN3/HsBPROS26 29.2(24.4) 69,77,78
7
11S(PA28)activatorcap
Systematic Othernames Mass[kDa] Literature
11Ssubunita REGaorPA28a 28.723 79,80
11Ssubunitb REGborPA28b 27.348 20
11Ssubunitg REGgorPA28g 30.886 81–84
19S(PA700)regulatorcap
Systematic Othernames Mass[kDa] Literature
ATPase-subunits
Rpt1 S7orp48,Mss1,Yta3,Cim5 48.633 85
Rpt2 S4orp56Yhs4,Yta5,Mts2 49.184 86–88
Rpt3 S6borp48,Tbp7,Yta2,Ynt1,MS73 47.336 89,90
Rpt4 S10borp42,Sug2,Pcs1,Crl13,CADp44 44.173 91,92
Rpt5 S6aorp50,Tbp1,Yta1 49.118 93,94
Rpt6 S8orp45,Trip1,Sug1,Cim3,Crl3,Tby1,Tbp10 45.653 95–97
Non-ATPase-subunits
Rpn1 S2orp97,Trap2,Nas1,Hrd2,Rpd1,Mts4 100.199 98
Rpn2 S1orp112,Sen3 105.866 99,100
Rpn3 S3orp58,Sun2 61.005 101
(Continues)