TIFA has dual functions in Helicobacter pylori ‐induced classical and alternative NF‐κB pathways

Abstract

Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor‐kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) via classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial cells. Tumor necrosis factor receptor‐associated factor (TRAF)‐interacting protein with forkhead‐associated domain (TIFA) was previously suggested to trigger classical NF‐κB activation, but its role in alternative NF‐κB activation remains unexplored. Here, we identify TRAF6 and TRAF2 as binding partners of TIFA, contributing to the formation of TIFAsomes upon H. pylori infection. Importantly, the TIFA/TRAF6 interaction enables binding of TGFβ‐activated kinase 1 (TAK1), leading to the activation of classical NF‐κB signaling, while the TIFA/TRAF2 interaction causes the transient displacement of cellular inhibitor of apoptosis 1 (cIAP1) from TRAF2, and proteasomal degradation of cIAP1, to facilitate the activation of the alternative NF‐κB pathway. Our findings therefore establish a dual function of TIFA in the activation of classical and alternative NF‐κB signaling in H. pylori‐infected gastric epithelial cells.

A20 undermines alternative NF-κB activity and expression of anti-apoptotic genes in Helicobacter pylori infection

“…2 b). These observations are consistent with our previous findings that the association of TIFA with the NIK regulatory complex is specific for H. pylori infection [ 18 ] and also suggest that the interaction of A20 with the NIK regulatory complex depends on TIFA.

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“…Accordingly, A20 interacts with TIFA within the TIFA/NIK regulatory complex, which in turn destabilizes the interaction of TIFA with the complex. This restores the stability of cIAP1 in the complex, an observation that is consistent with our previous findings [ 18 ]. This TIFA-free NIK regulatory complex recovers the ability to mediate the proteasomal degradation of NIK, leading to the shutdown of alternative NF-κB signaling.…”

“…We have recently shown that TIFA is crucial for H. pylori -induced alternative NF-κB activation. Specifically, the binding of TIFA to the NIK regulatory complex (TRAF3/TRAF2/cIAP1) supports the proteasome-dependent transient turnover of cIAP1 and the ensuing accumulation of NIK [ 18 ]. Thus, we asked whether A20 functions at this juncture in the alternative NF-κB signaling pathway.…”

“…Recently, the ADP-L-glycero-β- d -manno-heptose (ADP-heptose) of Gram-negative bacteria, a metabolic precursor of lipopolysaccharide, has been identified as the predominant trigger of the classical NF-κB pathway via binding to the cytosolic alpha-protein kinase 1 (ALPK1) [ 16 ]. The catalytic activity of ALPK1 is required for the self-oligomerization of tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA) [ 17 ], which together with TRAF6 and transforming growth factor β-activated kinase 1 (TAK1) activates the classical NF-κB pathway [ 18 ]. The ADP-heptose – ALPK1 – TIFA signaling module is also essential for alternative NF-κB activation by H. pylori .…”

“…The ADP-heptose – ALPK1 – TIFA signaling module is also essential for alternative NF-κB activation by H. pylori . We have recently shown that the binding of TIFA to the NIK regulatory complex facilitates the proteasome-dependent transient turnover of cIAP1, resulting in the stabilization of NIK [ 18 ].…”