title: p62/SQSTM1 enhances NOD2-mediated signaling and cytokine production through stabilizing NOD2 oligomerization.
abstract: NOD2 is a cytosolic pattern-recognition receptor that senses muramyl dipeptide of peptidoglycan that constitutes the bacterial cell wall, and plays an important role in maintaining immunological homeostasis in the intestine. To date, multiple molecules have shown to be involved in regulating NOD2 signaling cascades. p62 (sequestosome-1; SQSTM1) is a multifaceted scaffolding protein involved in trafficking molecules to autophagy, and regulating signal cascades activated by Toll-like receptors, inflammasomes and several cytokine receptors. Here, we show that p62 positively regulates NOD2-induced NF-κB activation and p38 MAPK, and subsequent production of cytokines IL-1β and TNF-α. p62 associated with the nucleotide binding domain of NOD2 through a bi-directional interaction mediated by either TRAF6-binding or ubiquitin-associated domains. NOD2 formed a large complex with p62 in an electron-dense area of the cytoplasm, which increased its signaling cascade likely through preventing its degradation. This study for the first time demonstrates a novel role of p62 in enhancing NOD2 signaling effects.
authors: Department of Microbiology and Immunology and Centre for Human Immunology, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, Canada.
authors: Sangwook
authors: S
authors: Park
authors: Soon-Duck
authors: SD
authors: Ha
authors: Macon
authors: M
authors: Coleman
authors: Shahab
authors: S
authors: Meshkibaf
authors: Sung Ouk
authors: SO
authors: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D021381:Protein Transport; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6