TIFA: a signaling hub linking inflammation, innate immunity, and human disease

The adaptor protein TRAF-interacting protein with a forkhead-associated domain (TIFA) has attracted growing interest because of its role in innate immune and inflammatory signaling. Functionally, TIFA facilitates the oligomerization and ubiquitination of TRAF6, which activates NF-κB-dependent inflammatory pathways. Additionally, the ALPK1-TIFA signaling pathway has been identified as a critical link between sensing microbial metabolites and initiating immune responses. Phosphorylation-dependent oligomerization of TIFA promotes the assembly of higher-order signaling complexes, thereby facilitating the recruitment of TRAF family proteins and the activation of multiple downstream pathways. Increasing evidence shows that TIFA is involved not only in inflammatory signaling but also in immune cell functions, chronic inflammation, tumor-related immune regulation, and blood cancers. Notably, TIFA exhibits context-dependent dual roles, functioning as an oncogenic factor in certain biological contexts while acting as a tumor suppressor in others. Therefore, this review summarizes the structural basis of TIFA activation, its signaling mechanisms, and its emerging roles in human disease, and discusses its therapeutic potential.