Molecules

# poly(I:C) module -------------------------------------------------------------------

PolyIC(Rigi,loc~ext~cyt)

PolyIC Rigi loc ext cyt
Rigi -- RIG-I-binding site,loc -- location (extracellular or intracellular cytoplasmic).

RIGI(Polyic,Mavs)

RIGI Polyic Mavs
Polyic -- poly(I:C)-binding site,Mavs -- MAVS-binding site.

MAVS(Rigi)

MAVS Rigi
Rigi -- RIG-I-binding site.

PKR(st~i~a)

PKR st i a
st -- activation state (switched on by poly(I:C) ternary complex).

OAS3(st~i~a)

OAS3 st i a
st -- activation state (switched on by poly(I:C) ternary complex).

RNaseL(st~i~a)

RNaseL st i a
st -- activation state (switched on by active OAS3).

eIF2a(st~0~p)

eIF2a st 0 p
st -- phosphorylation state (eIF2a is inhibited when phosphorylatedby active PKR)

RIGI_mRNA()

RIGI_mRNA

PKR_mRNA()

PKR_mRNA

OAS3_mRNA()

OAS3_mRNA

RNaseL_mRNA()

RNaseL_mRNA
# NF-kB module -----------------------------------------------------------------------

TNFa()

TNFa

TAK1(st~i~a)

TAK1 st i a
st -- activation state (activators: poly(I:C):RIG-I:MAVS, TNFa).

IKK(st~n~a~i~ii)

IKK st n a i ii
st -- activation state (one of: neutral, active, inactive, inactiveintermediate; activated by active TAK1).

IkBa(Nfkb,loc~nuc~cyt,Ser32_Ser36~0~pp)

IkBa Nfkb loc nuc cyt Ser32_Ser36 0 pp
in B-cells inhibitor, alpha; I[kappa]B[alpha]:loc -- subcellular location (nuclear or cytoplasmic),Ser32_Ser36 -- lumped phosphorylation site (phosphorylated by activeIKK; phosphorylated IkBa undergoes rapid degradation).

NFkB(Ikba,loc~nuc~cyt)

NFkB Ikba loc nuc cyt
Ikba -- binding site for IkBa,loc -- subcellular location (cytoplasmic or nuclear).

A20()

A20

IkBa_mRNA()

IkBa_mRNA

A20_mRNA()

A20_mRNA
# IRF3 module ------------------------------------------------------------------------

TBK1(Ser172~0~p)

TBK1 Ser172 0 p
Ser172 -- phosphosite (TBK1 is activated upon its phosphorylationinduced by poly(I:C):RIG-I:MAVS).

IRF3(Ser396~0~p)

IRF3 Ser396 0 p
Ser396 -- phosphosite (IRF3 is activated upon its phosphorylationby phosphorylated TBK1).# IFNb module ------------------------------------------------------------------------

IFNAR(Ifnb)

IFNAR Ifnb
Ifnb -- IFNb-binding site (IFNAR is activated upon IFNb binding).

IFNb(Ifnar,loc~ext~cyt)

IFNb Ifnar loc ext cyt

IFNAR_mRNA()

IFNAR_mRNA

IFNb_mRNA()

IFNb_mRNA
# STAT1/2 module ---------------------------------------------------------------------

STAT1(Stat2,Tyr701~0~p)

STAT1 Stat2 Tyr701 0 p
Stat2 -- binding site for STAT2,Tyr701 -- phosphosite (phosphorylated due to IFNAR:IFNb).

STAT2(Stat1,Tyr690~0~p)

STAT2 Stat1 Tyr690 0 p
Stat1 -- binding site for STAT1,Tyr690 -- phosphosite (phosphorylated due to IFNAR:IFNb).

STAT1_mRNA()

STAT1_mRNA

STAT2_mRNA()

STAT2_mRNA

Species

poly(I:C) module

PolyIC(Rigi,loc~ext)

PolyIC Rigi loc ext

RIGI(Mavs,Polyic)

RIGI Mavs Polyic

MAVS(Rigi)

MAVS Rigi

PKR(st~i)

PKR st i

OAS3(st~i)

OAS3 st i

RNaseL(st~i)

RNaseL st i

eIF2a(st~0)

eIF2a st 0

RIGI_mRNA()

RIGI_mRNA

PKR_mRNA()

PKR_mRNA

OAS3_mRNA()

OAS3_mRNA

RNaseL_mRNA()

RNaseL_mRNA
NF-kB module

TNFa()

TNFa

NFkB(Ikba!0,loc~cyt).IkBa(Nfkb!0,loc~cyt,Ser32_Ser36~0)

NFkB 0Ikba loc cyt IkBa 0Nfkb loc cyt Ser32_Ser36 0

TAK1(st~i)

TAK1 st i

IKK(st~n)

IKK st n

A20()

A20

IkBa_mRNA()

IkBa_mRNA

A20_mRNA()

A20_mRNA
IRF3 module

TBK1(Ser172~0)

TBK1 Ser172 0

IRF3(Ser396~0)

IRF3 Ser396 0
IFNb module

IFNAR(Ifnb)

IFNAR Ifnb

IFNb(Ifnar,loc~cyt)

IFNb Ifnar loc cyt

IFNb(Ifnar,loc~ext)

IFNb Ifnar loc ext

IFNAR_mRNA()

IFNAR_mRNA

IFNb_mRNA()

IFNb_mRNA
STAT1/2 module

STAT1(Stat2,Tyr701~0)

STAT1 Stat2 Tyr701 0

STAT2(Stat1,Tyr690~0)

STAT2 Stat1 Tyr690 0

STAT1(Stat2!1,Tyr701~p).STAT2(Stat1!1,Tyr690~p)

STAT1 1Stat2 Tyr701 p STAT2 1Stat1 Tyr690 p

STAT1_mRNA()

STAT1_mRNA

STAT2_mRNA()

STAT2_mRNA

Observables

# poly(I:C) module -------------------------------------------------------------------

RIGI(Mavs!?,Polyic!?)

RIGI Polyic Mavs

PKR()

PKR st i a

OAS3()

OAS3 st i a

RNaseL()

RNaseL st i a

RNaseL(st~a)

RNaseL st a

eIF2a()

eIF2a st 0 p

eIF2a(st~p)

eIF2a st p

RIGI_mRNA()

RIGI_mRNA

PKR_mRNA()

PKR_mRNA

OAS3_mRNA()

OAS3_mRNA

RNaseL_mRNA()

RNaseL_mRNA
# NF-kB module -----------------------------------------------------------------------

TAK1(st~a)

TAK1 st a

NFkB(loc~nuc,Ikba)

NFkB Ikba loc nuc

NFkB(loc~nuc)

NFkB Ikba loc nuc

NFkB()

NFkB Ikba loc nuc cyt

IkBa(Nfkb,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc Ser32_Ser36 0

IkBa(Nfkb,loc~nuc,Ser32_Ser36~pp)

IkBa Nfkb loc nuc Ser32_Ser36 pp

IkBa(Nfkb,loc~cyt,Ser32_Ser36~0)

IkBa Nfkb loc cyt Ser32_Ser36 0

IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb!+,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc Ser32_Ser36 0

IkBa(Nfkb!+,loc~nuc,Ser32_Ser36~pp)

IkBa Nfkb loc nuc Ser32_Ser36 pp

IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~0))

IkBa Nfkb loc cyt Ser32_Ser36 0

IkBa(Nfkb,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc Ser32_Ser36 0

IkBa(Nfkb,loc~nuc,Ser32_Ser36~pp)

IkBa Nfkb loc nuc Ser32_Ser36 pp

IkBa(Nfkb!+,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc Ser32_Ser36 0

IkBa(Nfkb!+,loc~nuc,Ser32_Ser36~pp))

IkBa Nfkb loc nuc Ser32_Ser36 pp

IkBa(Nfkb,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb,loc~cyt,Ser32_Ser36~0)

IkBa Nfkb loc cyt Ser32_Ser36 0

IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~0))

IkBa Nfkb loc cyt Ser32_Ser36 0

IkBa(Nfkb,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb,loc~cyt,Ser32_Ser36~0))

IkBa Nfkb loc cyt Ser32_Ser36 0

IkBa(Nfkb,loc~cyt,Ser32_Ser36~pp)

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~pp))

IkBa Nfkb loc cyt Ser32_Ser36 pp

IkBa(Nfkb,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc Ser32_Ser36 0

A20()

A20

IKK(st~a)

IKK st a

IkBa_mRNA()

IkBa_mRNA

A20_mRNA()

A20_mRNA
# IRF3 module ------------------------------------------------------------------------

IRF3()

IRF3 Ser396 0 p

IRF3(Ser396~p)

IRF3 Ser396 p
# IFNb module ------------------------------------------------------------------------

IFNAR()

IFNAR Ifnb

IFNAR(Ifnb!+)

IFNAR Ifnb

IFNb(loc~ext)

IFNb Ifnar loc ext

IFNb(loc~cyt)

IFNb Ifnar loc cyt

IFNAR_mRNA()

IFNAR_mRNA

IFNb_mRNA()

IFNb_mRNA
# STAT1/2 module ---------------------------------------------------------------------

STAT1()

STAT1 Stat2 Tyr701 0 p

STAT2()

STAT2 Stat1 Tyr690 0 p

STAT1(Tyr701~p)

STAT1 Stat2 Tyr701 p

STAT2(Tyr690~p)

STAT2 Stat1 Tyr690 p

STAT1(Stat2,Tyr701~0)

STAT1 Stat2 Tyr701 0

STAT2(Stat1,Tyr690~0)

STAT2 Stat1 Tyr690 0

STAT1(Stat2!1,Tyr701~p).STAT2(Stat1!1,Tyr690~p)

STAT1 1Stat2 Tyr701 p STAT2 1Stat1 Tyr690 p

STAT1_mRNA()

STAT1_mRNA

STAT2_mRNA()

STAT2_mRNA

Reaction Rules

## === Poly(I:C) MODULE ==============================================================(1) poly(I:C) enters the cell

PolyIC(Rigi,loc~ext) -> PolyIC(Rigi,loc~cyt)

PolyIC Rigi loc ext cyt take all branches, once each, in any order⬇⬇
(2) RIG-I binds poly(I:C)

RIGI(Mavs,Polyic) + PolyIC(Rigi,loc~cyt) -> RIGI(Mavs,Polyic!1).PolyIC(Rigi!1,loc~cyt)

RIGI 1 ⬇Polyic Mavs PolyIC 1 ⬇Rigi loc cyt
(3) poly(I:C)-bound RIG-I is degraded, freeing poly(I:C)(4) the poly(I:C):RIG-I complex binds MAVS, forming a ternary complex

RIGI(Mavs,Polyic!+) + MAVS(Rigi) -> RIGI(Mavs!1,Polyic!+).MAVS(Rigi!1)

RIGI Polyic 1 ⬇Mavs MAVS 1 ⬇Rigi
(5) RIG-I bound to both poly(I:C) and MAVS is degraded, protomers dissociate(6) poly(I:C) activates PKR

PolyIC(loc~cyt) + PKR(st~i) -> PolyIC(loc~cyt) + PKR(st~a)

PolyIC Rigi loc cyt PKR st i a take all branches, once each, in any order⬇⬇
(7) PKR inactivation

PKR(st~a) -> PKR(st~i)

PKR st i a take one or more branches, once each, in any order⬆⬆
(8) poly(I:C) activates OAS3

PolyIC(loc~cyt) + OAS3(st~i) -> PolyIC(loc~cyt) + OAS3(st~a)

PolyIC Rigi loc cyt OAS3 st i a take all branches, once each, in any order⬇⬇
(9) OAS3 inactivation

OAS3(st~a) -> OAS3(st~i)

OAS3 st i a take one or more branches, once each, in any order⬆⬆
(10A) active PKR phosphorylates eIF2a

PKR(st~a) + eIF2a(st~0) -> PKR(st~a) + eIF2a(st~p)

PKR st a eIF2a st 0 p take all branches, once each, in any order⬇⬇
(10B) eIF2a basal phosphorylation (=> activation of its inhibitory function)

eIF2a(st~0) -> eIF2a(st~p)

eIF2a st 0 p take all branches, once each, in any order⬇⬇
(11) eIF2a dephosphorylation

eIF2a(st~p) -> eIF2a(st~0)

eIF2a st 0 p take one or more branches, once each, in any order⬆⬆
(12) active OAS3 activates RNaseL

OAS3(st~a) + RNaseL(st~i) -> OAS3(st~a) + RNaseL(st~a)

OAS3 st a RNaseL st i a take all branches, once each, in any order⬇⬇
(13) RNase L deactivation

RNaseL(st~a) -> RNaseL(st~i)

RNaseL st i a take one or more branches, once each, in any order⬆⬆
(14, 15, 16, 17) transcription of IFN-stimulated genes (ISGs)(18, 19, 20, 21) mRNA degradation(22, 23, 24, 25) protein synthesis(26, 27, 28, 29) protein degradation## === NF-kB MODULE ==================================================================# --- activity of TAK1 -----------------------------------------------------(1A) poly(I:C):RIG-I:MAVS complex activates TAK1

RIGI(Mavs!1,Polyic!+).MAVS(Rigi!1) + TAK1(st~i) -> RIGI(Mavs!1,Polyic!+).MAVS(Rigi!1) + TAK1(st~a)

RIGI Polyic 1Mavs MAVS 1Rigi TAK1 st i a take all branches, once each, in any order⬇⬇
(1B) TNFa activates TAK1

TNFa() + TAK1(st~i) -> TNFa() + TAK1(st~a)

TNFa TAK1 st i a take all branches, once each, in any order⬇⬇
(2) active TAK1 is deactivated

TAK1(st~a) -> TAK1(st~i)

TAK1 st i a take one or more branches, once each, in any order⬆⬆
# --- activity of IKK ------------------------------------------------------(3) active TAK1 activates IKK

IKK(st~n) -> IKK(st~a)

IKK st n a take all branches, once each, in any order⬇⬇
(4) active IKK is deactivated, with a contribution from A20

IKK(st~a) -> IKK(st~i)

IKK st a i take all branches, once each, in any order⬇⬇
(5, 6) inactive IKK transitions to the neutral state

IKK(st~i) -> IKK(st~ii)

IKK st i ii take all branches, once each, in any order⬇⬇

IKK(st~ii) -> IKK(st~n)

IKK st n ii take one or more branches, once each, in any order⬆⬆
# --- formation of the IkBa:NF-kB complex ----------------------------------(7) IkBa and NF-kB form a complex in the cytoplasm

IkBa(Nfkb,loc~cyt,Ser32_Ser36~0) + NFkB(Ikba,loc~cyt) -> IkBa(Nfkb!1,loc~cyt,Ser32_Ser36~0).NFkB(Ikba!1,loc~cyt)

IkBa 1 ⬇Nfkb loc cyt Ser32_Ser36 0 NFkB 1 ⬇Ikba loc cyt
(8) IkBa and NF-kB form a complex in the nucleus

IkBa(Nfkb,loc~nuc,Ser32_Ser36~0) + NFkB(Ikba,loc~nuc) -> IkBa(Nfkb!1,loc~nuc,Ser32_Ser36~0).NFkB(Ikba!1,loc~nuc)

IkBa 1 ⬇Nfkb loc nuc Ser32_Ser36 0 NFkB 1 ⬇Ikba loc nuc
# --- phosphorylation of IkBa ----------------------------------------------(9) active IKK phosphorylates unbound IkBa

IKK(st~a) + IkBa(Nfkb,loc~cyt,Ser32_Ser36~0) -> IKK(st~a) + IkBa(Nfkb,loc~cyt,Ser32_Ser36~pp)

IKK st a IkBa Nfkb loc cyt Ser32_Ser36 0 pp take all branches, once each, in any order⬇⬇
(10) active IKK phosphorylates IkBa complexed with NF-kB

IKK(st~a) + IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~0) -> IKK(st~a) + IkBa(Nfkb!+,loc~cyt,Ser32_Ser36~pp)

IKK st a IkBa Nfkb loc cyt Ser32_Ser36 0 pp take all branches, once each, in any order⬇⬇
# --- degradation of IkBa --------------------------------------------------(11) phosphorylated unbound IkBa is degraded (in the cytoplasm)(12) phosphorylated NF-kB-bound IkBa is degraded (in the cytoplasm, releasing free NF-kB)(13) nonphosphorylated nonbound IkBa is degraded (in the cytoplasm)(14) nonphosphorylated NF-kB-bound IkBa is degraded (in the cytoplasm)# --- nucleocytoplasmic shuttling of NF-kB, IkBa, and IkBa:NF-kB -----------(15) nonbound NF-kB translocates from the cytoplasm to the nucleus

NFkB(Ikba,loc~cyt) -> NFkB(Ikba,loc~nuc)

NFkB Ikba loc nuc cyt take one or more branches, once each, in any order⬆⬆
(16) NF-kB bound to nonphosphorylated IkBa translocates from the nucleus to the cytoplasm

IkBa(Nfkb!1,loc~nuc,Ser32_Ser36~0).NFkB(Ikba!1,loc~nuc) -> IkBa(Nfkb!1,loc~cyt,Ser32_Ser36~0).NFkB(Ikba!1,loc~cyt)

IkBa 1Nfkb loc nuc cyt take all branches, once each, in any order⬇⬇ Ser32_Ser36 0 NFkB 1Ikba loc nuc cyt take all branches, once each, in any order⬇⬇
(17, 18) nonbound nonphosphorylated IkBa translocates between the cytoplasm and the nucleus

IkBa(Nfkb,loc~cyt,Ser32_Ser36~0) <-> IkBa(Nfkb,loc~nuc,Ser32_Ser36~0)

IkBa Nfkb loc nuc cyt take one or more branches, once each, in any order⬆⬆ Ser32_Ser36 0
# --- gene expression and degradation of transcripts -----------------------(19, 20) IkBa gene transcription and transcript degradation(21, 22) A20 gene transcription and transcript degradation# --- protein synthesis and degradation ------------------------------------(23) IkBa protein: synthesis(Degradation of IkBa protein is a part of signal transduction defined above; see rules 11--14.)(24, 25) A20 protein: synthesis and degradation## === IRF3 module ===================================================================(1) poly(I:C):RIG-I:MAVS complex activates (phosphorylates) TBK1

RIGI(Mavs!+,Polyic!+) + TBK1(Ser172~0) -> RIGI(Mavs!+,Polyic!+) + TBK1(Ser172~p)

RIGI Polyic Mavs TBK1 Ser172 0 p take all branches, once each, in any order⬇⬇
(2A) TBK1 is deactivated (dephosphorylated)

TBK1(Ser172~p) -> TBK1(Ser172~0)

TBK1 Ser172 0 p take one or more branches, once each, in any order⬆⬆
(2B) A20 (additionally) deactivates TBK1

A20() + TBK1(Ser172~p) -> A20() + TBK1(Ser172~0)

A20 TBK1 Ser172 0 p take one or more branches, once each, in any order⬆⬆
(3) TBK1 activates (phosphorylates) IRF3

TBK1(Ser172~p) + IRF3(Ser396~0) -> TBK1(Ser172~p) + IRF3(Ser396~p)

TBK1 Ser172 p IRF3 Ser396 0 p take all branches, once each, in any order⬇⬇
(4) IRF3 is deactivated (dephosphorylated)

IRF3(Ser396~p) -> IRF3(Ser396~0)

IRF3 Ser396 0 p take one or more branches, once each, in any order⬆⬆
## === IFNb module ===================================================================(1) IFNb binds IFNAR (autocrine activation)

IFNAR(Ifnb) + IFNb(Ifnar,loc~cyt) -> IFNAR(Ifnb!1).IFNb(Ifnar!1,loc~ext)

IFNAR 1 ⬇Ifnb IFNb 1 ⬇Ifnar loc ext cyt take one or more branches, once each, in any order⬆⬆
(2) IFNb binds IFNAR (external stimulation)

IFNAR(Ifnb) + IFNb(Ifnar,loc~ext) -> IFNAR(Ifnb!1).IFNb(Ifnar!1,loc~ext)

IFNAR 1 ⬇Ifnb IFNb 1 ⬇Ifnar loc ext
(3, 4) IFNAR1 gene transcription and transcript degradation(5, 6, 7) IFNAR protein: synthesis and degradation(8, 9): IFNb gene transcription and transcript degradation(10, 11): IFNb protein: synthesis and degradation## === STAT1/2 module ================================================================(1, 3; 2, 4) STAT1 and STAT2: phosphorylation and dephosphorylation

STAT1(Stat2,Tyr701~0) <-> STAT1(Stat2,Tyr701~p)

STAT1 Stat2 Tyr701 0 p take all branches, once each, in any order⬇⬇

STAT2(Stat1,Tyr690~0) <-> STAT2(Stat1,Tyr690~p)

STAT2 Stat1 Tyr690 0 p take all branches, once each, in any order⬇⬇
(5) p-STAT1 and p-STAT2 heterodimerize

STAT1(Stat2,Tyr701~p) + STAT2(Stat1,Tyr690~p) -> STAT1(Stat2!1,Tyr701~p).STAT2(Stat1!1,Tyr690~p)

STAT1 1 ⬇Stat2 Tyr701 p STAT2 1 ⬇Stat1 Tyr690 p
(6) the p-STAT1:p-STAT2 dimer gets dephosphorylated and then immediately dissociates

STAT1(Stat2!1,Tyr701~p).STAT2(Stat1!1,Tyr690~p) -> STAT1(Stat2,Tyr701~0) + STAT2(Stat1,Tyr690~0)

STAT1 1 ⬆Stat2 Tyr701 0 p take one or more branches, once each, in any order⬆⬆ STAT2 1 ⬆Stat1 Tyr690 0 p take one or more branches, once each, in any order⬆⬆
(7, 8; 9, 10) STAT1 gene and STAT2 gene transcription and transcript degradation(11, 12; 13, 14; 15) STAT1 protein and STAT2 protein: synthesis and degradation