SLC15A4 acts as a signaling scaffold, recruiting the adapter TASL to the cytosolic surface of endolysosomes (Heinz LX. et al., 2020; Custodio TF et al., 2023; Zhang H et al., 2023; Chen X et al., 2023). Upon activation of endosomal Toll-like receptors (TLR7, TLR8, and TLR9), the pre-formed SLC15A4:TASL complex facilitates recruitment and phosphorylation of IRF5 (Heinz L. et al., 2020). Several studies have identified kinases involved in the phosphorylation of IRF5, including IKBKB (IKKβ), a catalytic subunit of the IkB kinase complex (CHUK:IKBKB:IKBKG), which is activated by various endogenous and exogenous stimuli, such as TLR ligands, cytokines and growth factors (Pauls E et al., 2012). The kinase activity of IKBKB (IKKβ) phosphorylates IRF5 at Ser446 (refers to the UniProtKB canonical sequence) in myeloid cells such as macrophages in response to TLR ligands (Lopez-Pelaez M et al., 2014; Ren J et al., 2014). IRAK4 and TAK1, two kinases that function upstream of IKBKB, control TLR-induced IKBKB (IKKβ) kinase activity and thus IRF5 activity in human monocytes (Cushing L et al., 2017; Bergstrøm B et al., 2015). The kinase activity of IKKα (CHUK) is believed to be dispensable for IRF5 activation (Lopez-Pelaez M et al., 2014; Ren J et al., 2014; Heinz LX. et al., 2020). IRF5 can also be phosphorylated by TBK1, IKBKE (IKKε) (Yang C et al., 2022; Ryzhakov G et al., 2021). Furthermore, LYN, a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B-lymphocytes and myeloid cells, has been found to suppress the transcriptional activity of IRF5 in the TLR-MyD88 pathway (Ban T et al., 2016) via LYN-directed IRF5 degradation (Tawaratsumida K et al., 2022).
Phosphorylated IRF5 (p-S446-IRF5) then forms homodimers and translocates to the nucleus to stimulate production of type I interferons and pro-inflammatory cytokines.
