Table 2.

Host-derived endogenous negative regulators of TLR-signalling-mediated inflammatory pathways generating cytokine storm and sepsis. See text for details.

Host-derived negative regulators of TLR signalling	Category/Classification	Target/Mode of action
1.TAG	Splice variant of TRAM	Competes with TRAM for binding to TRIF.
2.SARM	TIR-domain containing adaptor molecule	Binds and inhibits TRIF-dependent TLR signalling
3.IRF4 or MUM1	IFN regulatory factor (IRF) family of transcription factors	Inhibits IRF5 binding to MyD88 and TRAF6 and its translocation to nucleus
4.TIPE2	Member of TNF-α-induced protein-8 (TNFAIP8) family	Inhibits TLR signalling via binding to CASP8 and inhibiting NF-κB and AP-1 activation
5.DAP12	Transmembrane adaptor protein	DAP12 mediated inhibition of TLR signalling involves another adaptor protein called DOK-3
6.DOK1 and DOK2	Adaptor Proteins	Inhibit Ras-Erk dependent signalling
7.Axl	TAM family of receptor kinases	Inhibits NF-κB mediated production of TNF-α
8.IRAK-M	Member of serine/threonine kinase family	Inhibits dissociation of IRAK1 and IRAK-4 form MyD88 and formation of IRAK-TRAF6 complex
9.TOLLIP	Adaptor protein that interacts with cytoplasmic TIR domain of IL-1Rs	Inhibits phosphorylation and kinase activity of IRAK1
10.SHP-1	Intracellular tyrosine phosphatase	Inhibits MAP kinase and NF-κB activation through binding to IRAK1
11.Calcineurin	A serine/threonine phosphatase	Specific pathway unknown
12.PTP1B	Intracellular tyrosine phosphatase	Inhibits MAPKs, NF-κB and IRF3
13.A20 (TNFAIP3)	Ubiquitin modifying enzyme	Inhibits NF-κB signalling as a negative feedback via removing ubiquitin moieties from TRAF6
14.CYLD	Tumour suppressor deubiquitinase	Inhibits TLR2 signalling via inhibiting MyD88, TRAF2, TRAF6 TRAF7 and NEMO
15.USP4	Deubiquitinase	Inhibits TRL4 signalling via deubiquinating TRAF6 and inhibiting its adaptor function
16.USP18 or UBP43 or ISG15 isopeptidase	Isopeptidase	Cleaves the K63-linked polyubiquitin chains of TAK1 and also targets NEMO
17.DUBA or OUTD5	Cysteine protease	Removes K63-ubiquitin chain from TRAF3 to inhibit NF-κB and IRF3 activation
18.NR4A1 or Nur77	Member of nuclear receptor 4A receptor subfamily	Prevent auto-ubiquitination of TRAF6 via binding to TRAF6
19.NR4A2 or Nurr1	Member of nuclear receptor 4A receptor subfamily	Inhibits NF-κB activation downstream to TLR4 signalling
20.SHP or NR0B2	Orphan nuclear receptor	Prevents Lys63-linked polyubiquitination of TRAF6 and subsequent activation of NF-κB
21.MSK1 and 2	Nuclear kinase sharing homology with ribosomal S6 kinase (p90rsk) family	Phosphorylate histone H3 and CREB that negatively regulates TLR signalling and induces several anti-inflammatory genes
22.TANK	TRAF binding protein	Binding of TANK to TRAF6 inhibits NF-κB and AP-1 activation
23.PDLIM-2 (Mystique and SLIM in mice)	PDZ and LIM domain containing Alkaline Phosphatase	Inhibits TLR signalling by acting as a nuclear E3 ubiquitin ligase and inhibits NF-κB activation
24.MKRN2 or RNF62	Zinc finger and RING finger domain containing nuclear protein	Binds to PDLIM2 and inhibits activation of NF-κB downstream to TLR signalling
25.PDLIM1 or CLP36 or Elfin	PDZ and LIM domain containing protein of APL subfamily	Inhibits NF-κB activation by sequestering p65 into cytosol
26.TRIM30α	A member of tripartite-motif (TRIM) protein family	Inhibits TRAF6 autoubiquitination by degrading TAB2 and TAB3and suppresses NF-κB activation
27.TRIM8	Acts as ubiquitin E3 ligase	Polyubiquitinates TRIF and inhibits TRIF-TBK1 interaction
28.Triad3A	RING finger type E3 ubiquitin ligase	Degrades TLR proteins
29.NLRX1	Member of NLR family	Binds to IKK complex causing an inhibition of IKKα and IKKβ phosphorylation and NF-κB activation
30.NLRC3 or NOD3	Member of NLR family	It interacts with TRAF6 to attenuate its K63-linked ubiquitination to inhibit NF-κB activation
31.NLRC5	Member of NLR family	Inhibits IKK complexes to inhibit NF-κB activation and type 1 IFN signalling pathways
32.ST2	Serves as a part of IL-33 receptor	Binds to sequester MyD88 and MAL without affecting TRIF and IRAK to inhibit TLR-induced NF-κB activation
33.SIGIRR or TIR-8 (IL-1R8)	Member of TLR/IL-1R superfamily	Inhibits TLR-mediated NF-κB and JNK activation via blocking the IRAK and TRAF6 recruitment to MyD88
34.TLR10	Member of TLR family	Activates PI3K/Akt/IL-1R antagonist pathway and also inhibits MyD88 and TRIF-dependent signaling pathways
35.ATF3	Member of activating transcription factor/cAMP response element family of bZip transcription factors	Bind to consensus c-AMP response element (CRE) sequences
36.IL-37	Member of IL-1 cytokine family	Inhibits NF-κB and MAPK activation