The GOLD Domain-containing Protein TMED1 Is Involved in Interleukin-33 Signaling*

Background: A putative association between the trafficking protein TMED1 and the IL-33 receptor ST2L has previously been reported; however, the functional consequence of this remained unknown. Results: TMED1 binds ST2L, and TMED1 knockdown impairs IL-33-induced IL-8 and IL-6 production. Conclusion: TMED1 is required for optimal IL-33-induced signal activation. Significance: These results further implicate the TMED family as an important family in immune signaling pathways. The proinflammatory danger signal IL-33, which is released from damaged or dying cells, achieves its effects via the IL-1R family member ST2L. The detection of IL-33 by ST2L initiates downstream signaling pathways that result in the activation of MAPKs and NF-κB. Here, we show that TMED1 associates with ST2L. Using a series of mutation and deletion constructs, we demonstrate that this interaction is mediated by the GOLD domain of TMED1 and the TIR domain of ST2L. Our findings also demonstrate that TMED1 is required for optimal IL-33-induced IL-8 and IL-6 production. This discovery provides additional support to the concept that the TMED family members are important players in innate immune signaling.

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