Reactome | SLC15A4:TASL-dependent IRF5 activation

SLC15A4:TASL-dependent IRF5 activation

Stable Identifier

R-HSA-9860276

DOI

10.3180/R-HSA-9860276.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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This Reactome module describes the Toll-like receptor 7 (TLR7), TLR8, or TLR9 – induced activation of interferon regulatory factor 5 (IRF5) via the SLC15A4:TASL axis.

Solute carrier family 15, member 4 (SLC15A4, also known as PHT1) is a proton-coupled L-histidine/oligopeptide transporter. In addition to its function as a transporter, SLC15A4 regulates TLR7-9 signaling pathways in late endosomes/lysosomes (Heinz LX. et al., 2020; Kobayashi T et al., 2021). SLC15A4 acts as a signaling scaffold, recruiting the protein TLR adaptor interacting with SLC15A4 on the lysosome (TASL) to the cytosolic surface of endolysosomes (Heinz LX. et al., 2020; Custodio TF et al., 2023; Chen X et al., 2023). Upon activation of endosomal TLR signaling, TASL undergoes phosphorylation and recruits IRF5 to its pLxIS motif (Heinz LX. et al., 2020). The SLC15A4:TASL complex facilitates IRF5 phosphorylation by IKBKB (IKKβ) and subsequent IRF5 homodimerization downstream of TLR7-TLR9 (Heinz LX. et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Once activated, IRF5 translocates to the nucleus to induce the transcription of genes encoding type I interferons (IFNs) and pro-inflammatory cytokines. Hyperactivation of the SLC15A4:TASL:IRF5 pathway, often caused by the detection of endogenous nucleic acids, leads to increased production of type I IFNs and is associated with pathogenesis of inflammatory diseases such as systemic lupus erythematosus (SLE) (Odhams CA et al., 2019; Heinz LX. et al., 2020; Kobayashi T et al., 2021).
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Literature References

PubMed ID	Title	Journal	Year
37527038	SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL Zhang, H, Rebsamen, M, Eibel, H, Bernaleau, L, Hasanovic, E, Delacrétaz, M, Drobek, A	Cell Rep	2023
32433612	TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9 Mbow, ML, Bensimon, A, Bigenzahn, JW, Sedlyarov, V, Rebsamen, M, Kapoor, U, Superti-Furga, G, Essletzbichler, P, Li, J, Heinz, LX, Pizzagalli, MD, Girardi, E, César-Razquin, A, Lee, J, Goldmann, U, Müller, AC, Scorzoni, S, Papakostas, K, Stefanovic, A, Whitehurst, CE, Kartnig, F, King, FJ	Nature	2020
37863913	Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling Xie, M, Rebsamen, M, Superti-Furga, G, Deng, H, Monguió-Tortajada, M, Chen, X, Yang, M, Tian, X, Zhang, S, Delacrétaz, M, Ding, Q, Na, J, Liu, C, Zhou, B, Yin, J, Chang, Q, Yang, Z, Liu, X, Zeng, W, Xu, L, Wang, Y, Zhang, Y, Song, M, Dong, L	Nat Commun	2023