TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6.

E3 ligase TRAF6 plays a critical role in TLRs trigged M1 macrophage activation. However, the function of TRAF6 in IL-4-induced M2 macrophage activation has not been illuminated. We report here that deficiency of TRAF6 significantly impaired IL-4-induced genes expression in macrophage. Mechanistically, TRAF6 mediated the protein stability of a key factor in IL-4 signaling. Overexpression of TRAF6 increased protein level, conversely, knockdown or knockout of endogenous TRAF6 decreased it. Further study showed that TRAF6 bound duanyu18136 by TRAF6 C domain and reduced K48-ubiquitination of duanyu18136 which could induce degradation of duanyu18136, explaining why TRAF6 could conduct duanyu18136 stability. Intriguingly, the E3 ligase activity of TRAF6 was dispensable for stabilizing duanyu18136, despite TRAF6 promoted its K63 ubiquitination. These results indicate that TRAF6 is essential for duanyu18136 stability in IL-4 signaling and may act as a positive regulator in both M1 and M2 polarization.

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