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maiwald

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Manuscript information

Combining theoretical analysis and experimental data generation reveals IRF9 as a crucial factor for accelerating interferon α-induced early antiviral signalling.

  • Tim Maiwald
  • Annette Schneider
  • Hauke Busch
  • Sven Sahle
  • Norbert Gretz
  • Thomas S Weiss
  • Ursula Kummer
  • Ursula Klingmüller
FEBS J. 2010; 277 (22): 4741-4754
Abstract
Type I interferons (IFN) are important components of the innate antiviral response. A key signalling pathway activated by IFNα is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Major components of the pathway have been identified. However, critical kinetic properties that facilitate accelerated initiation of intracellular antiviral signalling and thereby promote virus elimination remain to be determined. By combining mathematical modelling with experimental analysis, we show that control of dynamic behaviour is not distributed among several pathway components but can be primarily attributed to interferon regulatory factor 9 (IRF9), constituting a positive feedback loop. Model simulations revealed that increasing the initial IRF9 concentration reduced the time to peak, increased the amplitude and enhanced termination of pathway activation. These model predictions were experimentally verified by IRF9 over-expression studies. Furthermore, acceleration of signal processing was linked to more rapid and enhanced expression of IFNα target genes. Thus, the amount of cellular IRF9 is a crucial determinant for amplification of early dynamics of IFNα-mediated signal transduction.

Unit definitions 2

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name Definition
— —
— 60.0 second

Compartments 1

Id Name Spatial dimensions Size
default_compartment — 3.0 1.0

Species 39

Id Name Initial quantity Compartment Fixed
ActivatedReceptorComplex ActivatedReceptorComplex 0.0 AU default_compartment ✘
ActivatedReceptorComplexSTAT2c ActivatedReceptorComplexSTAT2c 0.0 AU default_compartment ✘
ActivatedReceptorComplexSTAT2cSTAT1c ActivatedReceptorComplexSTAT2cSTAT1c 0.0 AU default_compartment ✘
CP CP 20.0 AU default_compartment ✘
IFN IFN 0.0 AU default_compartment ✘
IFNARdimer IFNARdimer 0.0 AU default_compartment ✘
IRF9c IRF9c 45.0 AU default_compartment ✘
IRF9n IRF9n 0.0 AU default_compartment ✘
ISGF3c ISGF3c 0.0 AU default_compartment ✘
ISGF3cCP ISGF3cCP 0.0 AU default_compartment ✘
ISGF3n ISGF3n 0.0 AU default_compartment ✘
ISGF3nNP ISGF3nNP 0.0 AU default_compartment ✘
JAK JAK 26.0 AU default_compartment ✘
NP NP 40.0 AU default_compartment ✘
OccupiedISGF3nbindingsites OccupiedISGF3nbindingsites 0.0 AU default_compartment ✘
OccupiedISGF3nbindingsitesNP OccupiedISGF3nbindingsitesNP 0.0 AU default_compartment ✘
OpenISGF3nbindingsites OpenISGF3nbindingsites 500.0 AU default_compartment ✘
PIAS PIAS 10.0 AU default_compartment ✘
PIASISGF3n PIASISGF3n 0.0 AU default_compartment ✘
ReceptorIFNAR1 ReceptorIFNAR1 1000.0 AU default_compartment ✘
ReceptorJAKcomplex ReceptorJAKcomplex 0.0 AU default_compartment ✘
ReceptorTYKcomplex ReceptorTYKcomplex 0.0 AU default_compartment ✘
SOCS1 SOCS1 0.0 AU default_compartment ✘
STAT1c STAT1c 1500.0 AU default_compartment ✘
STAT1cstarSTAT2cstar STAT1cstarSTAT2cstar 0.0 AU default_compartment ✘
STAT1cstarSTAT2cstarCP STAT1cstarSTAT2cstarCP 0.0 AU default_compartment ✘
STAT1n STAT1n 0.0 AU default_compartment ✘
STAT1nstarSTAT2nstar STAT1nstarSTAT2nstar 0.0 AU default_compartment ✘
STAT1nstarSTAT2nstarNP STAT1nstarSTAT2nstarNP 0.0 AU default_compartment ✘
STAT2c STAT2c 250.0 AU default_compartment ✘
STAT2cIRF9 STAT2cIRF9 0.0 AU default_compartment ✘
STAT2n STAT2n 250.0 AU default_compartment ✘
STAT2nIRF9 STAT2nIRF9 0.0 AU default_compartment ✘
TYK TYK 13.0 AU default_compartment ✘
extVariable extVariable 0.0 AU default_compartment ✔
mRNAc mRNAc 0.0 AU default_compartment ✘
mRNAn mRNAn 0.0 AU default_compartment ✘
preIFN preIFN 6.5 AU default_compartment ✘
species6 species6 1000.0 AU default_compartment ✘

Initial assignments 0

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition
Reactions 41
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
v_1 v_1 {0.5}ReceptorIFNAR1 + {0.5}TYK = {0.5}ReceptorTYKcomplex

cytoplasm * (k1 * ReceptorIFNAR1 * TYK - k2 * ReceptorTYKcomplex)
v_10 — {0.5}ISGF3c = ISGF3n

k19*ISGF3c-k29*ISGF3n
v_11 — {0.5}STAT1cstarSTAT2cstar = STAT1nstarSTAT2nstar

PhosphoTransport*STAT1cstarSTAT2cstar-k210*STAT1nstarSTAT2nstar
v_12 — STAT1nstarSTAT2nstar + IRF9n = ISGF3n

nucleus*(k111*STAT1nstarSTAT2nstar*IRF9n-k211*ISGF3n)
v_13 — OpenISGF3nbindingsites + ISGF3n = OccupiedISGF3nbindingsites

nucleus*(k112*OpenISGF3nbindingsites*ISGF3n-k212*OccupiedISGF3nbindingsites)
v_14 v_14 extVariable = mRNAn

nucleus * function4Transcription
v_15 — mRNAn = {0.5}mRNAc

k114*mRNAn-k214*mRNAc
v_16 v_16 extVariable = {0.5}IRF9c

cytoplasm * function4
v_17 v_17 extVariable = {0.5}SOCS1

cytoplasm * function6
v_18 v_18 {0.5}ActivatedReceptorComplex = {0.5}ReceptorIFNAR1 + {0.5}species6 + {0.5}JAK + {0.5}TYK

cytoplasm * function5
v_19 — {0.5}ActivatedReceptorComplex = {0.5}IFNARdimer

cytoplasm*k118*ActivatedReceptorComplex
v_2 — {0.5}JAK + {0.5}species6 = {0.5}ReceptorJAKcomplex

cytoplasm*(k11*JAK*species6-k21*ReceptorJAKcomplex)
v_20 — IRF9n = extVariable

nucleus*IRF9deg*IRF9n
v_21 — {0.5}STAT2cIRF9 = {0.5}STAT2c

cytoplasm*IRF9deg*STAT2cIRF9
v_22 — STAT2nIRF9 = STAT2n

nucleus*IRF9deg*STAT2nIRF9
v_23 — {0.5}ISGF3c + {0.5}CP = {0.5}ISGF3cCP

cytoplasm*(k122*ISGF3c*CP-k222*ISGF3cCP)
v_24 — {0.5}ISGF3cCP = {0.5}STAT1c + {0.5}STAT2c + {0.5}CP + {0.5}IRF9c

cytoplasm*k123*ISGF3cCP
v_25 — {0.5}STAT1cstarSTAT2cstar + {0.5}CP = {0.5}STAT1cstarSTAT2cstarCP

cytoplasm*(k124*STAT1cstarSTAT2cstar*CP-k224*STAT1cstarSTAT2cstarCP)
v_26 — {0.5}STAT1cstarSTAT2cstarCP = {0.5}STAT1c + {0.5}STAT2c + {0.5}CP

cytoplasm*k125*STAT1cstarSTAT2cstarCP
v_27 — NP + STAT1nstarSTAT2nstar = STAT1nstarSTAT2nstarNP

nucleus*(NPfreebinding*NP*STAT1nstarSTAT2nstar-NPfreeunbinding*STAT1nstarSTAT2nstarNP)
v_28 — STAT1nstarSTAT2nstarNP = STAT1n + STAT2n + NP

nucleus*k127*STAT1nstarSTAT2nstarNP
v_29 — ISGF3n + NP = ISGF3nNP

nucleus*(NPfreebinding*ISGF3n*NP-NPfreeunbinding*ISGF3nNP)
v_3 — {0.5}ReceptorJAKcomplex + {0.5}ReceptorTYKcomplex + {0.5}IFN = {0.5}IFNARdimer

cytoplasm*(k12*ReceptorJAKcomplex*ReceptorTYKcomplex*IFN-k22*IFNARdimer)
v_30 — ISGF3nNP = STAT1n + STAT2n + NP + IRF9n

nucleus*k129*ISGF3nNP
v_31 — NP + OccupiedISGF3nbindingsites = OccupiedISGF3nbindingsitesNP

nucleus*(k130*NP*OccupiedISGF3nbindingsites-k230*OccupiedISGF3nbindingsitesNP)
v_32 — OccupiedISGF3nbindingsitesNP = STAT1n + STAT2n + IRF9n + OpenISGF3nbindingsites + NP

nucleus*k131*OccupiedISGF3nbindingsitesNP
v_33 — PIAS + ISGF3n = PIASISGF3n

nucleus*(k132*PIAS*ISGF3n-k232*PIASISGF3n)
v_34 — {0.5}mRNAc = extVariable

cytoplasm*k133*mRNAc
v_35 — STAT1n = {0.5}STAT1c

k134*STAT1n-k234*STAT1c
v_36 — STAT2n = {0.5}STAT2c

k135*STAT2n-k235*STAT2c
v_37 — {0.5}STAT2c + {0.5}IRF9c = {0.5}STAT2cIRF9

cytoplasm*(k136*STAT2c*IRF9c-k236*STAT2cIRF9)
v_38 — STAT2n + IRF9n = STAT2nIRF9

nucleus*(k137*STAT2n*IRF9n-k237*STAT2nIRF9)
v_39 — {0.5}STAT2cIRF9 = STAT2nIRF9

k138*STAT2cIRF9-k238*STAT2nIRF9
v_4 — {0.5}IFNARdimer = {0.5}ActivatedReceptorComplex

cytoplasm*k13*IFNARdimer
v_40 — {0.5}IRF9c = IRF9n

k139*IRF9c-k239*IRF9n
v_41 — {0.5}preIFN = {0.5}IFN

cytoplasm*k140*preIFN
v_5 — {0.5}STAT2cIRF9 + {0.5}ActivatedReceptorComplex = {0.5}ActivatedReceptorComplexSTAT2c + {0.5}IRF9c

cytoplasm*statrecbinding*STAT2cIRF9*ActivatedReceptorComplex
v_6 — {0.5}STAT2c + {0.5}ActivatedReceptorComplex = {0.5}ActivatedReceptorComplexSTAT2c

cytoplasm*(statrecbinding*STAT2c*ActivatedReceptorComplex-statrecunbinding*ActivatedReceptorComplexSTAT2c)
v_7 — {0.5}STAT1c + {0.5}ActivatedReceptorComplexSTAT2c = {0.5}ActivatedReceptorComplexSTAT2cSTAT1c

cytoplasm*(statrecbinding*STAT1c*ActivatedReceptorComplexSTAT2c-statrecunbinding*ActivatedReceptorComplexSTAT2cSTAT1c)
v_8 — {0.5}ActivatedReceptorComplexSTAT2cSTAT1c = {0.5}ActivatedReceptorComplex + {0.5}STAT1cstarSTAT2cstar

cytoplasm*k17*ActivatedReceptorComplexSTAT2cSTAT1c
v_9 — {0.5}IRF9c + {0.5}STAT1cstarSTAT2cstar = {0.5}ISGF3c

cytoplasm*(k18*IRF9c*STAT1cstarSTAT2cstar-k28*ISGF3c)

Parameters 0   75

Global parameters

Id Value
DNAbinding 0.0
IRF9deg 0.0001
NPfreebinding 0.01
NPfreeunbinding 0.1
PhosphoTransport 0.015
ReceptorSOCSdeg 0.000012
Receptordegradation 0.0003
SOCSbinding 0.02
SOCSunbinding 0.1
STAT1Start 1500.0
STAT2Start 250.0
StartingJak 26.0
StartingReceptor 1000.0
StartingTyk 13.0
activatedsynth 0.045
constdeg 0.0005
cytoplasm 2.0
function4 —
function4Transcription —
function5 —
function6 —
k1 0.1
k11 0.1
k111 0.01
k112 0.1
k113 0.000025
k114 0.001
k118 0.01
k12 0.01
k122 0.001
k123 0.003
k124 0.001
k125 0.003
k127 0.1
k129 0.002
k13 0.005
k130 0.0001
k131 0.1
k132 0.1
k133 0.0005
k134 0.01
k135 0.0014
k136 0.01
k137 0.01
k138 0.00125
k139 0.02
k140 0.0009
k17 8.0
k18 0.1
k19 0.015
k2 0.05
k21 0.05
k210 0.0
k211 0.01
k212 0.1
k214 0.0
k22 0.01
k222 0.2
k224 0.2
k230 0.1
k232 0.1
k234 0.00125
k235 0.0000817
k236 0.01
k237 0.01
k238 0.0014
k239 0.005
k28 0.1
k29 0.0
nucleus 1.0
startkin 13.0
statrecbinding 0.002
statrecunbinding 4.0
vactivated 0.045
vconst 0.005

Local parameters

Id Value Reaction

Rules 0   0   5

Assignment rules

Definition
DNAbinding = OccupiedISGF3nbindingsites * 2
function6 = activatedsynth*mRNAc-constdeg*SOCS1
function4Transcription = k1*OccupiedISGF3nbindingsites
function5 = ActivatedReceptorComplex*Receptordegradation+ActivatedReceptorComplex*ReceptorSOCSdeg*SOCS1
function4 = vconst+mRNAc*vactivated-IRF9c*IRF9deg

Rate rules

Definition

Algebraic rules

Definition

Events 0

Trigger Assignments