Modulation of Toll‐like receptor 4 signaling by a novel adaptor protein STAP‐2 in macrophages

Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein, that contains pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-κB activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its SH2-like domain, bound to both MyD88 and IKK-α/β, but not TRAF6 or IRAK1, and formed a functional complex composed of MyD88-STAP-2-IKK-α/β. These interactions augmented MyD88- and/or IKK-α/β-dependent signals, leading to enhancement of the NF-κB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-κB activation instead of the TRAF6-IRAK1pathway.