Activated IKBKB phosphorylates IRF5

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). <p>Phosphorylated IRF5 (p-S446-IRF5) then forms homodimers and translocates to the nucleus to stimulate production of type I interferons and pro-inflammatory cytokines.

SLC15A4作为一种信号支架蛋白，负责将适配蛋白TASL招募至内溶酶体的细胞质表面（Heinz LX. et al., 2020；Custodio TF et al., 2023；Zhang H et al., 2023；Chen X et al., 2023）。在内溶酶体Toll样受体（TLR7、TLR8和TLR9）的激活过程中，预形成的SLC15A4:TASL复合物促进了IRF5的招募和磷酸化（Heinz L. et al., 2020）。多项研究已鉴定出参与IRF5磷酸化的激酶，包括IKBKB（IKKβ），它是IKB激酶复合体（CHUK:IKBKB:IKBKG）的催化亚基，该复合体可被多种内源性和外源性刺激激活，如TLR配体、细胞因子和生长因子（Pauls E et al., 2012）。IKBKB（IKKβ）的激酶活性将IRF5在Ser446位点（参照UniProtKB的规范序列）磷酸化，这是在响应TLR配体时骨髓细胞（如巨噬细胞）中的一种现象（Lopez-Pelaez M et al., 2014；Ren J et al., 2014）。IRAK4和TAK1这两种激酶在上游调控IKBKB（IKKβ）的激酶活性，进而调控人单核细胞中的IRF5活性（Cushing L et al., 2017；Bergstrøm B et al., 2015）。IKKα（CHUK）的激酶活性被认为对于IRF5的激活并非必需（Lopez-Pelaez M et al., 2014；Ren J et al., 2014；Heinz LX. et al., 2020）。IRF5还可以被TBK1、IKBKE（IKKε）磷酸化（Yang C et al., 2022；Ryzhakov G et al., 2021）。此外，LYN，一种在调节B淋巴细胞和骨髓细胞内的信号通路中发挥重要作用的Src家族酪氨酸激酶，被发现通过LYN介导的IRF5降解途径抑制TLR-MyD88通路中IRF5的转录活性（Ban T et al., 2016；Tawaratsumida K et al., 2022）。磷酸化的IRF5（p-S446-IRF5）随后形成同源二聚体并转移至细胞核，从而刺激I型干扰素和促炎细胞因子的产生。