TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6. (November 2020)

• Record Type: Journal Article
• Authors: Zhou, Chenchen; Lu, Cheng; Pu, Huangsheng; Li, Dongyu; Zhang, Luo
• Is Part Of: Molecular immunology. Volume 127(2020:Nov.)
• Page Start: 223
• Page End: 229
• Publication Date: 2020-11
• Subjects: TRAF6 -- STAT6 -- IL-4 -- M2 macrophage -- Macrophage polarization; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2020.09.001
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: Depletion of TRAF6 results in defective expression of IL-4-induced M2 macrophage markers. TRAF6 regulates STAT6 protein stability. TRAF6 associates with STAT6 by TRAF6 C domain. TRAF6 enhances STAT6 K63 ubiquitination but reduces STAT6 K48 ubiquitination. Abstract: 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 STAT6, a key factor in IL-4 signaling. Overexpression of TRAF6 increased STAT6 protein level, conversely, knockdown or knockout of endogenous TRAF6 decreased it. Further study showed that TRAF6 bound STAT6 by TRAF6 C domain and reduced K48-ubiquitination of STAT6 which could induce degradation of STAT6, explaining why TRAF6 could conduct STAT6 stability. Intriguingly, the E3 ligase activity of TRAF6 was dispensable for stabilizing STAT6, despite TRAF6 promoted its K63 ubiquitination. These results indicate that TRAF6 is essential for STAT6 stability in IL-4 signaling and may act as a positive regulator in both M1 and M2 polarization.