TLR2-dependent selective autophagy regulates NF-κB lysosomal degradation in hepatoma-derived M2 macrophage differentiation

• Published in: Cell death and differentiation Vol. 20; no. 3; pp. 515 - 523
• Main Authors: Chang, C-P, Su, Y-C, Hu, C-W, Lei, H-Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2013; Nature Publishing Group
• Subjects: 631/136/142; 631/208/200; 631/80/474; 631/80/82/39; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amyotrophic lateral sclerosis; Animals; Apoptosis; Autophagy; Autophagy-Related Protein 5; Biochemistry; Biomedical and Life Sciences; Bone Marrow Cells - cytology; Carcinoma, Hepatocellular - metabolism; Cell Biology; Cell Cycle Analysis; Cell Differentiation; Cell Line, Tumor; Culture Media, Conditioned - pharmacology; Cytokines - metabolism; Female; Life Sciences; Lysosomes - drug effects; Lysosomes - metabolism; Macrolides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Original Paper; Phosphorylation; RNA Interference; RNA, Small Interfering - metabolism; Sequestosome-1 Protein; Stem Cells; Toll-Like Receptor 2 - metabolism; Transcription Factor RelA - metabolism; NF; p62/SQSTM1; B; extracellular signal-regulated kinase 1/2 (ERK1/2); selective autophagy; TLR2
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.146

Autophagy is a lysosomal pathway for cellular homeostasis control. Both non-selective bulk autophagy and selective autophagy of specific proteins or organelles have been found. Selective autophagy prevents cells from pathogen invasion and stress damage, but its role in regulating transcriptional factors is not clear. Using a macrophage cell differentiation model, the role of autophagy in nuclear factor- κ B (NF- κ B) regulation is investigated. The bone marrow-derived macrophages (BMDMs) will differentiate into a M2-like phenotype in the presence of hepatoma tumor cell condition medium (CM). The TLR2 signaling drives this M2 polarization and causes NF- κ B p65 degradation via lysosome-dependent pathway. The CM-induced ubiquitinated- NF- κ B p65 forms aggresome-like structures (ALS) in the cytoplasm of cultured and hepatoma-associated M2 macrophages. This NF- κ B p65-contained ALS is recognized by p62/SQSTM1 and degraded by selective autophagy. Treatment with the lysosomal inhibitor bafilomycin A1 or the knockdown of Atg5 can prevent CM-induced NK- κ B p65 degradation and induce M2 macrophages to produce a high level of pro-inflammatory cytokines. Furthermore, TLR2 signal induces sustained phosphorylation of extracellular signal-regulated kinase 1/2 to facilitate this autophagy-dependent NF- κ B regulation. Our finding provides a novel pathway of NF- κ B regulation by p62/SQSTM1-mediated selective autophagy.