Abstract
The degradation of target proteins by small molecules utilizing the cellular proteolytic system is featured as a treatment strategy of several diseases. We found that S-1-propenylcysteine (S1PC) among several cysteine derivatives in aged garlic extract inhibited TLR-mediated IL-6 production by inducing the degradation of adaptor protein MyD88. We showed that S1PC directly denatured MyD88 and induced the formation of protein aggregates. Consequently, MyD88 was degraded by aggresome-autophagy pathway. On the other hand, S-allylcysteine, a structural analog of S1PC, failed to induce the degradation of MyD88 because of its inability to denature MyD88 although it also activated autophagy. Our findings suggest that S1PC induces MyD88 degradation through the denaturation of MyD88 and the activation of autophagy. Thus, S1PC may serve as the base to develop a therapeutic means for immune diseases associated with aberrant TLR signaling pathways.
Highlights
Autophagy plays an important role in the degradation of protein aggregates and damaged organelles, and helps maintain protein quality control (PQC)[14,15,16,17]
We found that S1PC inhibited LPS-induced IL-6 production in a concentration-dependent manner (Fig. 1b), whereas other compounds tested were ineffective
S1PC reduced the phosphorylation of IL-1 receptor-associated kinase 4 (IRAK4) and NF-κB p65, the downstream signaling molecules of myeloid differentiation response protein 88 (MyD88), whereas it had no effect on the total protein levels of IRAK4 and NF-κB p65 (Fig. 1c)
Summary
Autophagy plays an important role in the degradation of protein aggregates and damaged organelles, and helps maintain protein quality control (PQC)[14,15,16,17]. Protein aggregates are post-translationally modified by the process such as ubiquitination, and they are delivered to aggresome by binding to histone deacetylase 6 (HDAC6)[18,19]. They are degraded by the selective macroautophagy known as aggrephagy[3]. TLR dimerization induced by binding of its ligands recruits myeloid differentiation response protein 88 (MyD88), a common adaptor protein of TLRs, and IL-1 receptor-associated kinase 4 (IRAK4) to plasma membrane. We report that S1PC inhibited lipopolysaccharides (LPS)-induced TLR4 signaling pathway by inducing MyD88 degradation through its denaturation and the activation of autophagy
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