XIAP-associated Factor 1 (XAF1) Regulates TNF Receptor 1 Complex Stability

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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.