CIAP1-Dependent TRAF2 Degradation Is Required for Macrophage Differentiation and Function

Abstract

TRAF2 (Tumor necrosis factor (TNF) Receptor associated factor) is an adaptor molecule involved in TNF family membrane receptor signalling pathway. We demonstrate that TRAF2 is required for macrophage differentiation. Its silencing prevents Iκ-Bα degradation, NF-κB p65 nuclear translocation and the differentiation process. Then, TRAF2 is degraded by the proteasome system in the cytoplasm. Inhibition or silencing of the E3 ubiquitine ligase cIAP1 from the IAP (Inhibitor of apoptosis protein) family of proteins, prevents the differentiation-associated TRAF2-degradation. In the presence of proteasome inhibitor, TRAF2 colocalizes with cIAP1 in a golgi-associated compartment, suggesting that cIAP-1-mediated TRAF2 degradation occurred in this subcellular compartment. An overexpression of TRAF2 or silencing of cIAP1 prevents the outcome of differentiation as revealed by the expression of differentiation markers at the cell surface, and inhibits the secretion of pro-inflammatory cytokines such as interleukin-8 and MCP-1 by fully differentiated-macrophages in response to CD40 stimulation. Our data suggest that TRAF2 expression and its subsequent cIAP1-dependent degradation is required for the differentiation of monocytes into macrophages and allows the macrophages to be fully functional.