Reactome | SLC15A4 binds TASL

SLC15A4 binds TASL

Stable Identifier

R-HSA-9860295

Type

Reaction [binding]

Species

Homo sapiens

Compartment

endolysosome membrane, cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 7/8 (TLR7/8) Cascade (Homo sapiens)
      - SLC15A4:TASL-dependent IRF5 activation (Homo sapiens)
        
        SLC15A4 binds TASL (Homo sapiens)
    - Toll Like Receptor 9 (TLR9) Cascade (Homo sapiens)
      - SLC15A4:TASL-dependent IRF5 activation (Homo sapiens)
        
        SLC15A4 binds TASL (Homo sapiens)

General

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Solute carrier family 15 member 4 protein (SLC15A4, also known as PHT1) and TLR adaptor interacting with SLC15A4 on the lysosome (TASL) control the activation of the key transcription factor IRF5 in response to activation of endosomal Toll-like receptors (TLR7, TLR8, and TLR9) (Heinz L et al., 2020; Zhang H et al., 2023). TASL is recruited to SLC15A4, located on the endolysosomal membrane (Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Structural studies using cryo-electron microscopy (cryo-EM) reveal that formation of the human SLC15A4:TASL complex involves transition of SLC15A4 from the endolysosomal lumen-exposed outward-facing apo state to an inward-facing state in which the negatively-charged binding pocket of SLC15A4 facilitates the insertion of the N-terminal helix of TASL (Chen X et al., 2023; Boeszoermeny A et al., 2023). Mutagenesis analysis further confirms that the N-terminus of TASL interacts with SLC15A4 (Heinz L et al., 2020; Zhang H et al., 2023; Boeszoermeny A et al., 2023; Chen X et al., 2023). Similar findings have been reported for chicken SLC15A4 and TASL (Custodio TF et al., 2023). The formation of SLC15A4:TASL complex is required for endosomal TLR-induced IRF5 activation, and subsequent translocation of activated IRF5 to the nucleus (Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Disruption of the SLC15A4:TASL complex abolishes TLR-induced IRF5 activation (Heinz L. et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023).

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