title: X-linked inhibitor of apoptosis-associated factor 1 regulates TNF receptor 1 complex stability.
abstract: X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a cytokine-regulated, tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain-containing protein that has a poorly defined cellular function. Here, we show that ectopically expressed XAF1 inhibits TNF-ɑ-induced NF-κB activation, whereas shRNA silencing of endogenous XAF1 augments it. Our data suggest that XAF1 may inhibit TNF-ɑ-induced NF-κB activation by disrupting the assembly of the TRADD/TRAF2/RIP1 complex (complex I) downstream of TNF receptor activation. XAF1 interacts with TRAF2 and inhibits TRAF2-dependent NF-κB activation, in part, by blocking TRAF2 polyubiquitination. Our findings also indicate that although XAF1 does not directly inhibit RIP1-dependent NF-κB activation, it binds RIP1 and disrupts RIP1/TRADD association. Our data suggest that XAF1 acts as a feedback regulator of the TNF receptor signaling pathway to suppress NF-κB activation.
authors: Department of Biological Sciences, The University of Toledo, OH, USA.
authors: Boren
authors: B
authors: Lin
authors: Department of Biological Sciences, The University of Toledo, OH, USA.
authors: Da
authors: D
authors: Xu
authors: Department of Biological Sciences, The University of Toledo, OH, USA.
authors: Douglas W
authors: DW
authors: Leaman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C417551:XAF1 protein, human
keywords: Receptor interacting protein kinase 1; XIAP associated factor 1; inflammatory response; nuclear factor-kappa B; tumor necrosis factor; tumor necrosis factor receptor-associated factor 2