TRAF3/STAT6 axis regulates macrophage polarization and tumor progression.

Abstract

Converting tumor-associated macrophages (TAMs) from the M2 to the M1 phenotype is considered an effective strategy for cancer therapy. TRAF3 is known to regulate NF-κB signaling. However, the role of TRAF3 in TAM polarization has not yet been completely elucidated. Here, we found that ablation of TRAF3 increased M1 markers, iNOS, FGR and SLC4A7, while down-regulated M2 markers, CD206, CD36 and ABCC3, expression levels in macrophages. Moreover, TRAF3 deficiency enhanced LPS-induced M1 and abolished IL-4-induced macrophage polarization. Next, quantitative ubiquitomics assays demonstrated that among the quantitative 7618 ubiquitination modification sites on 2598 proteins, ubiquitination modification of IL-4 responding proteins was the most prominently reduced according to enrichment analysis. STAT6, a key factor of IL-4 responding protein, K450 and K129 residue ubiquitination levels were dramatically decreased in TRAF3-deficient macrophages. Ubiquitination assay and luciferase assay demonstrated that TRAF3 promotes STAT6 ubiquitination and transcriptional activity. Site mutation analysis revealed STAT6 K450 site ubiquitination played a vital role in TRAF3-mediated STAT6 activation. Finally, B16 melanoma mouse model demonstrated that myeloid TRAF3 deficiency suppressed tumor growth and lung metastasis in vivo. Taken together, TRAF3 plays a vital role in M2 polarization via regulating STAT6 K450 ubiquitination in macrophages.

• Authors: Jian-Hong Shi, Li-Na Liu, Dan-Dan Song, Wen-Wen Liu, Chen Ling, Fei-Xiang Wu, Ting-Ting Wang, Bin Liu, Nai-Peng Cui, Yan Qin, Zhi-Yu Ni
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 30 Issue 8 Pg. 2005-2016 (08 2023) ISSN: 1476-5403 [Electronic] England
• PMID: 37474750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Chemical References

• Interleukin-4
• TNF Receptor-Associated Factor 3

Topics

• Mice
• Animals
• Interleukin-4 (pharmacology, metabolism)
• TNF Receptor-Associated Factor 3 (genetics, metabolism, pharmacology)
• Macrophages (metabolism)
• Signal Transduction
• Phenotype
• Macrophage Activation