TY - JOUR TI - Domain fusion TLR2-4 enhances the autophagy-dependent clearance of Staphylococcus aureus in the genetic engineering goat AU - Wang, Mengyao AU - Qi, Yu AU - Cao, Yutao AU - Zhang, Xiaosheng AU - Wang, Yongsheng AU - Liu, Qingyou AU - Zhang, Jinlong AU - Zhou, Guangbin AU - Ai, Yue AU - Wei, Shao AU - Wang, Linli AU - Liu, Guoshi AU - Lian, Zhengxing AU - Han, Hongbing A2 - Stallings, Christina L A2 - Taniguchi, Tadatsugu A2 - Li, Kui VL - 11 PY - 2022 DA - 2022/06/28 SP - e78044 C1 - eLife 2022;11:e78044 DO - 10.7554/eLife.78044 UR - https://doi.org/10.7554/eLife.78044 AB - Staphylococcus aureus infections pose a potential threat to livestock production and public health. A novel strategy is needed to control S. aureus infections due to its adaptive evolution to antibiotics. Autophagy plays a key role in degrading bacteria for innate immune cells. In order to promote S. aureus clearance via Toll-like receptor (TLR)-induced autophagy pathway, the domain fusion TLR2-4 with the extracellular domain of TLR2, specific recognizing S. aureus, and transmembrane and intracellular domains of TLR4 is assembled, then the goat expressing TLR2-4 is generated. TLR2-4 substantially augments the removal of S. aureus within macrophages by elevating autophagy level. Phosphorylated JNK and ERK1/2 promote LC3-puncta in TLR2-4 macrophages during S. aureus-induced autophagy via MyD88 mediated the TAK1 signaling cascade. Meantime, the TRIF-dependent TBK1-TFEB-OPTN signaling is involved in TLR2-4-triggered autophagy after S. aureus challenge. Moreover, the transcript of ATG5 and ATG12 is significantly increased via cAMP-PKA-NF-κB signaling, which facilitates S. aureus-induced autophagy in TLR2-4 macrophages. Overall, the novel receptor TLR2-4 enhances the autophagy-dependent clearance of S. aureus in macrophages via TAK1/TBK1-JNK/ERK, TBK1-TFEB-OPTN, and cAMP-PKA-NF-κB-ATGs signaling pathways, which provide an alternative approach for resistant against S. aureus infection. KW - Toll-like receptor 2-4 KW - Staphylococcus aureus KW - autophagy KW - macrophages KW - goat JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -