Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

Zhengzheng Yan, Haihua Luo, Bingyao Xie, Tian Tian, Shan Li, Zhixia Chen, Jinghua Liu, Xuwen Zhao, Liyong Zhang, Yongqiang Deng, Timothy R. Billiar () and Yong Jiang ()
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Zhengzheng Yan: Southern Medical University
Haihua Luo: Southern Medical University
Bingyao Xie: Southern Medical University
Tian Tian: Southern Medical University
Shan Li: Southern Medical University
Zhixia Chen: University of Pittsburgh School of Medicine
Jinghua Liu: Southern Medical University
Xuwen Zhao: Southern Medical University
Liyong Zhang: University of Pittsburgh School of Medicine
Yongqiang Deng: Southern Medical University
Timothy R. Billiar: University of Pittsburgh School of Medicine
Yong Jiang: Southern Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

Date: 2021
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DOI: 10.1038/s41467-020-20577-3

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