Abstract
The cationic antimicrobial peptide epinecidin-1 was identified from Epinephelus coioides and possesses multiple biological functions, including antibacterial, antifungal, anti-tumor, and immunomodulatory effects. In addition, epinecidin-1 suppresses lipopolysaccharide (LPS)-induced inflammation by neutralizing LPS and ameliorating LPS/Toll-like receptor (TLR)-4 internalization. However, it is unclear whether the actions of epinecidin-1 depend on the regulation of TLR adaptor protein MyD88 or endogenous TLR signaling antagonists, which include A20, interleukin-1 receptor associated kinase (IRAK)-M, and suppressor of cytokine signaling (SOCS)-1. Our results demonstrate that epinecidin-1 alone does not affect A20, IRAK-M, or SOCS-1 protein levels. However, pre-incubation of epinecidin-1 significantly inhibits LPS-induced upregulation of A20, IRAK-M, and SOCS-1. In addition, epinecidin-1 significantly reduces the abundance of MyD88 protein. Both MG132 (a specific proteasome inhibitor) and Heclin (a specific Smurf E3 ligase inhibitor) are able to abolish epinecidin-1-mediated MyD88 degradation. Thus, our data suggest that epinecidin-1 directly inhibits MyD88 via induction of the Smurf E3 ligase proteasome pathway.
Highlights
Toll-like receptor (TLR) signaling is crucial for modulating innate and adaptive immune responses in physiological and pathological conditions [1]
To determine determinewhether whether protein of endogenous were upon stimulation, Raw264.7 macrophage cells were treated with for different and the increased upon LPS stimulation, Raw264.7 macrophage cells were treated with LPStimes, for different protein levels
suppressor of cytokine signaling (SOCS)-1 (Figure 3A,D) were attenuated by epinecidin-1. These results suggest that epinecidin-1 does were attenuated by epinecidin-1. These results suggest that epinecidin-1 does not directly regulate not directly directly regulate regulate the the abundance abundance of of A20, interleukin-1 receptor-associated kinase (IRAK)-M, and and SOCS-1, SOCS-1, pre-incubation pre-incubation of of not the abundance of A20, IRAK-M, and SOCS-1, pre-incubation of epinecidin-1 can blunt epinecidin-1 can blunt
Summary
Toll-like receptor (TLR) signaling is crucial for modulating innate and adaptive immune responses in physiological and pathological conditions [1]. While TLR-mediated inflammatory responses are essential for the elimination of pathogens [1], over-activation of TLR signaling may contribute to the etiology of inflammatory disorders, such as inflammatory bowel diseases [10], chronic inflammation [11], cytokine storm [12], and autoimmune diseases [13]. Endogenous TLR signaling antagonists can serve as signaling brakes to prevent the over-activation of TLR-signaling These antagonists include zinc finger protein A20, IRAK-M, suppressor of cytokine signaling (SOCS)-1, and others [14]. Among these inhibitors, A20 suppresses TLR signaling by triggering TRAF-6 degradation [15], while IRAK-M
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