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 phosphorylated
by 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, inactive
intermediate; 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 active
IKK; 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 phosphorylation
induced by poly(I:C):RIG-I:MAVS).

IRF3(Ser396~0~p)

IRF3 Ser396 0 p

Ser396 -- phosphosite (IRF3 is activated upon its phosphorylation
by 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 Ikba loc cyt IkBa Nfkb 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 Stat2 Tyr701 p STAT2 Stat1 Tyr690 p

STAT1_mRNA()

STAT1_mRNA

STAT2_mRNA()

STAT2_mRNA

Observables


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

RIG_I_total RIGI(Mavs!?,Polyic!?)

RIGI ?Polyic ?Mavs

PKR_total PKR()

PKR st i ?a

OAS3_total OAS3()

OAS3 st i ?a

RNaseL_total RNaseL()

RNaseL st i ?a

RNaseL_a RNaseL(st~a)

RNaseL st a

eIF2a_total eIF2a()

eIF2a st 0 ?p

eIF2a_p eIF2a(st~p)

eIF2a st p

RIGI_mRNA RIGI_mRNA()

RIGI_mRNA

PKR_mRNA PKR_mRNA()

PKR_mRNA

OAS3_mRNA OAS3_mRNA()

OAS3_mRNA

RNaseL_mRNA RNaseL_mRNA()

RNaseL_mRNA

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

TAK1_a TAK1(st~a)

TAK1 st a

NFkB_nuc_free NFkB(loc~nuc,Ikba)

NFkB Ikba loc nuc

NFkB_nuc_total NFkB(loc~nuc)

NFkB ?Ikba loc nuc

NFkB_total NFkB()

NFkB ?Ikba loc nuc ?cyt

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc nuc Ser32_Ser36 0

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

IkBa Nfkb loc nuc Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 0

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc nuc Ser32_Ser36 0

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

IkBa Nfkb loc nuc Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 0

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

IkBa Nfkb loc nuc Ser32_Ser36 0

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

IkBa Nfkb loc nuc Ser32_Ser36 pp

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

IkBa Nfkb loc nuc Ser32_Ser36 0

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

IkBa Nfkb loc nuc Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 0

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 0

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 0

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc cyt Ser32_Ser36 pp

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

IkBa Nfkb loc nuc Ser32_Ser36 0

A20 A20()

A20

IKK_a IKK(st~a)

IKK st a

IkBa_mRNA IkBa_mRNA()

IkBa_mRNA

A20_mRNA A20_mRNA()

A20_mRNA

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

IRF3_total IRF3()

IRF3 Ser396 0 ?p

IRF3_p IRF3(Ser396~p)

IRF3 Ser396 p

# IFNb module ------------------------------------------------------------------------

IFNAR_total IFNAR()

IFNAR ?Ifnb

IFNAR_a IFNAR(Ifnb!+)

IFNAR Ifnb

IFNb_ext IFNb(loc~ext)

IFNb ?Ifnar loc ext

IFNb_cyt IFNb(loc~cyt)

IFNb ?Ifnar loc cyt

IFNAR_mRNA IFNAR_mRNA()

IFNAR_mRNA

IFNb_mRNA IFNb_mRNA()

IFNb_mRNA

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

STAT1_total STAT1()

STAT1 ?Stat2 Tyr701 0 ?p

STAT2_total STAT2()

STAT2 ?Stat1 Tyr690 0 ?p

STAT1_p STAT1(Tyr701~p)

STAT1 ?Stat2 Tyr701 p

STAT2_p STAT2(Tyr690~p)

STAT2 ?Stat1 Tyr690 p

STAT1_u STAT1(Stat2,Tyr701~0)

STAT1 Stat2 Tyr701 0

STAT2_u STAT2(Stat1,Tyr690~0)

STAT2 Stat1 Tyr690 0

STAT12_dimer STAT1(Stat2!1,Tyr701~p).STAT2(Stat1!1,Tyr690~p)

STAT1 Stat2 Tyr701 p STAT2 Stat1 Tyr690 p

STAT1_mRNA STAT1_mRNA()

STAT1_mRNA

STAT2_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 ⬇Polyic Mavs ⬇ PolyIC ⬇Rigi loc cyt

(3) poly(I:C)-bound RIG-I is degraded, freeing poly(I:C)

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

RIGI ⬆Polyic Mavs degraded ⬆ PolyIC ⬆Rigi loc cyt

(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 ⬇Mavs ⬇ MAVS ⬇Rigi

(5) RIG-I bound to both poly(I:C) and MAVS is degraded, protomers dissociate

PolyIC(Rigi!1,loc~cyt).RIGI(Mavs!2,Polyic!1).MAVS(Rigi!2) -> PolyIC(Rigi,loc~cyt) + MAVS(Rigi)

PolyIC ⬆Rigi loc cyt ⬆ RIGI ⬆Polyic ⬆Mavs degraded ⬆ MAVS ⬆Rigi

(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)

0 -> RIGI_mRNA()

RIGI_mRNA synthesized

0 -> PKR_mRNA()

PKR_mRNA synthesized

0 -> OAS3_mRNA()

OAS3_mRNA synthesized

0 -> RNaseL_mRNA()

RNaseL_mRNA synthesized

(18, 19, 20, 21) mRNA degradation

RIGI_mRNA() -> 0

RIGI_mRNA degraded

PKR_mRNA() -> 0

PKR_mRNA degraded

OAS3_mRNA() -> 0

OAS3_mRNA degraded

RNaseL_mRNA() -> 0

RNaseL_mRNA degraded

(22, 23, 24, 25) protein synthesis

RIGI_mRNA() -> RIGI_mRNA() + RIGI(Mavs,Polyic)

RIGI_mRNA RIGI Polyic Mavs synthesized

PKR_mRNA() -> PKR_mRNA() + PKR(st~i)

PKR_mRNA PKR st i synthesized

OAS3_mRNA() -> OAS3_mRNA() + OAS3(st~i)

OAS3_mRNA OAS3 st i synthesized

RNaseL_mRNA() -> RNaseL_mRNA() + RNaseL(st~i)

RNaseL_mRNA RNaseL st i synthesized

(26, 27, 28, 29) protein degradation

RIGI(Mavs,Polyic) -> 0

RIGI Polyic Mavs degraded

PKR() -> 0

PKR st i ?a degraded

OAS3() -> 0

OAS3 st i ?a degraded

RNaseL() -> 0

RNaseL st i ?a degraded

## === 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 Mavs MAVS Rigi 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 ⬇Nfkb loc cyt Ser32_Ser36 0 ⬇ NFkB ⬇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 ⬇Nfkb loc nuc Ser32_Ser36 0 ⬇ NFkB ⬇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)

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

IkBa Nfkb loc cyt Ser32_Ser36 pp degraded

(12) phosphorylated NF-kB-bound IkBa is degraded (in the cytoplasm, releasing free NF-kB)

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

IkBa ⬆Nfkb loc cyt Ser32_Ser36 pp degraded ⬆ NFkB ⬆Ikba loc cyt

(13) nonphosphorylated nonbound IkBa is degraded (in the cytoplasm)

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

IkBa Nfkb loc cyt Ser32_Ser36 0 degraded

(14) nonphosphorylated NF-kB-bound IkBa is degraded (in the cytoplasm)

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

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

# --- 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 Nfkb loc nuc cyt take all branches, once each, in any order⬇ Ser32_Ser36 0 NFkB Ikba 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

0 -> IkBa_mRNA()

IkBa_mRNA synthesized

IkBa_mRNA() -> 0

IkBa_mRNA degraded

(21, 22) A20 gene transcription and transcript degradation

0 -> A20_mRNA()

A20_mRNA synthesized

A20_mRNA() -> 0

A20_mRNA degraded

# --- protein synthesis and degradation ------------------------------------
(23) IkBa protein: synthesis

IkBa_mRNA() -> IkBa_mRNA() + IkBa(Nfkb,loc~cyt,Ser32_Ser36~0)

IkBa_mRNA IkBa Nfkb loc cyt Ser32_Ser36 0 synthesized

(Degradation of IkBa protein is a part of signal transduction defined above; see rules 11--14.)
(24, 25) A20 protein: synthesis and degradation

A20_mRNA() -> A20_mRNA() + A20()

A20_mRNA A20 synthesized

A20() -> 0

A20 degraded

## === 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 ⬇Ifnb ⬇ IFNb ⬇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 ⬇Ifnb ⬇ IFNb ⬇Ifnar loc ext

(3, 4) IFNAR1 gene transcription and transcript degradation

0 <-> IFNAR_mRNA()

IFNAR_mRNA synthesized

(5, 6, 7) IFNAR protein: synthesis and degradation

IFNAR_mRNA() -> IFNAR_mRNA() + IFNAR(Ifnb)

IFNAR_mRNA IFNAR Ifnb synthesized

IFNAR(Ifnb) -> 0

IFNAR Ifnb degraded

IFNAR(Ifnb!+) -> 0

IFNAR Ifnb degraded

(8, 9): IFNb gene transcription and transcript degradation

0 -> IFNb_mRNA()

IFNb_mRNA synthesized

IFNb_mRNA() -> 0

IFNb_mRNA degraded

(10, 11): IFNb protein: synthesis and degradation

IFNb_mRNA() -> IFNb_mRNA() + IFNb(Ifnar,loc~cyt)

IFNb_mRNA IFNb Ifnar loc cyt synthesized

IFNb(Ifnar,loc~cyt) -> 0

IFNb Ifnar loc cyt degraded

## === 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 ⬇Stat2 Tyr701 p ⬇ STAT2 ⬇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 ⬆Stat2 Tyr701 0 p take one or more branches, once each, in any order⬆ ⬆ STAT2 ⬆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

0 -> STAT1_mRNA()

STAT1_mRNA synthesized

0 -> STAT2_mRNA()

STAT2_mRNA synthesized

STAT1_mRNA() -> 0

STAT1_mRNA degraded

STAT2_mRNA() -> 0

STAT2_mRNA degraded

(11, 12; 13, 14; 15) STAT1 protein and STAT2 protein: synthesis and degradation

STAT1_mRNA() -> STAT1_mRNA() + STAT1(Stat2,Tyr701~0)

STAT1_mRNA STAT1 Stat2 Tyr701 0 synthesized

STAT2_mRNA() -> STAT2_mRNA() + STAT2(Stat1,Tyr690~0)

STAT2_mRNA STAT2 Stat1 Tyr690 0 synthesized

STAT1(Stat2) -> 0

STAT1 Stat2 Tyr701 0 ?p degraded

STAT2(Stat1) -> 0

STAT2 Stat1 Tyr690 0 ?p degraded

STAT1(Stat2!1).STAT2(Stat1!1) -> 0

STAT1 ⬆Stat2 Tyr701 0 ?p degraded ⬆ STAT2 ⬆Stat1 Tyr690 0 ?p degraded