Table 1.
Alternate splice forms that encode negative regulators in the TLR signaling pathway.
| Gene | Pro | Anti | Species | Event | Effect of PAMP | Notes | Reference |
|---|---|---|---|---|---|---|---|
| MD-2 | MD-2 | MD-2B | Mouse & Rat | 54 bp (18 aa) deletion 5’ end exon 3 | Not induced by LPS (data not shown) | Inhibits NF-κB reporter, binds TLR4, prevents TLR4 from reaching surface | (49, 50) |
| MD-2 | MD-2 | MD-2s | Human | exon 2 skip | Induced by LPS, IFNγ, IL-6 | Inhibits LPS-induced NF-κB reporter & IL-8 production, binds LPS & TLR4, competitively inhibits binding of MD-2 to TLR4 | (51) |
| TLR4 | TLR4 | smTLR4 | Mouse | additional exon between exons 2 & 3 | Induced by LPS | In frame stop produces truncated soluble protein. Inhibits LPS-induced NF-κB reporter & TNF production | (52) |
| TLR3 | TLR3 | unnamed | Human | Inhibitory isoform lacks 1,622 bp | Induced by Type I Interferons | Inhibits poly(I:C)-induced signaling | (53) |
| MyD88 | MyD88-L | MyD88-S | Mouse & Human | exon 2 skip | Induced by multiple stimuli – see Figure 5 | Inhibits LPS and IL1β-induced NF-κB activation. | (54–58) |
| TRAM | TRAM | TAG | Human & other primates | alternate splice site in exon 4 | Decreased 1 hr post-LPS, then rebounds by 2 hrs in HEK293 cells expressing TLR4, MD2, and CD14 | Inhibits LPS-induced ISRE but not NF-κB reporter. Inhibits TRAM by displacing TRIF | (59) |
| IRAK1 | IRAK1 | IRAK1c | Human | exon 11 skip | Induced by LPS in monos & DCs | Lacks kinase activity, not phosphorylated by IRAK4, can bind IRAK2, MyD88, Tollip, and TRAF6. Inhibits NF-κB, AP1, and LPS/CpG-induced cytokine production. | (60) |
| IRAK2 | IRAK2 | IRAK2c | Mouse | Alternate transcription start site leads to loss of exons 1-3, longer 5’UTR in exon 4 | Induced by LPS | Inhibits NF-κB | (61) |
| IRAK2 | IRAK2 | IRAK2d | Mouse | exon 2 skip & 30bp deletion 5’ end of exon 12 | Not reported | Inhibits NF-κB | (61) |
| IKKγ | IKKγ | IKKγΔ | Human | exon 5 skip | Induced by virus infection but not as much as WT isoform | Complex. May depend on cell type - see text. | (62–64) |
| IKKβ | IKKβ | IKKβb | Mouse & Human | Intron 15 retention | Not reported | siRNA indicates is negative regulator. | (65) |
| TBK1 | TBK1 | TBK1s | Mouse & Human | exon 3-6 skip | Induced by Sendai virus (SeV) infection | binds RIG-I, disrupts RIG-I-VISA interaction, inhibits IRF3 activation | (66) |
| IKKε | IKKε | IKKε-sv1 | Human | exon 21 skip | Induced by TNF | Forms dimers with IKKε-wt, inhibits IKKε-induced IRF3 signaling including anti-viral activity. Fails to interact with TANK, NAP1, or SINTBAD. | (67) |
| IKKε | IKKε | IKKε-sv2 | Human | exon 20 skip | Induced by TNF | Forms dimers with IKKε-wt, inhibits IKKε-induced IRF3 signaling including anti-viral activity. Fails to interact with TANK, NAP1, or SINTBAD. | (67) |
| NF-κB p65 | p65 | p65Δ | Mouse & Human | Alternate splicing deletes 30 bp (10 aa) at 5’ end of an exon | Not reported | Inhibits NF-κB dimerization and NF-κB activity | (68, 69) |
| p38α | p38α | EXIP | Mouse & Human | exon 10 and 11 skip | Not reported | Inhibits NF-κB activation | (70) |
| IRF3 | IRF3 | IRF3a | Human | Additional exon between exons 2 & 3 | Not reported | Inhibits virus-induced IRF3 activity and IFNβ expression | (71, 72) |
| IRF3 | IRF3 | IRF3-CL | Human | Alternate 3’ splice site leads to the addtion of 16 bp to 5’ end of exon 7 | Not reported | Inhibits virus-induced IRF3 activity and IFNβ expression | (73) |
| IRF3 | IRF3 | IRF3-nirs3 | Human | exon 6 skip | Not reported | Inhibits virus-induced IRF3 activity and IFNβ expression | (74, 75) |
| IRF3 | IRF3 | IRF3f | Human | exon 2 skip | Not reported | Inhibits IRF3 | (74) |
“Pro” is name of the canonical pro-inflammatory isoform. “Anti” is the name of the alternative splice form that encodes the negative regulator of signaling.