TIFA and TIFAB: FHA-domain proteins involved in inflammation, hematopoiesis, and disease.

Forkhead-associated (FHA) domain-containing proteins are widely expressed across eubacteria and in eukaryotes. FHA domains contain phosphopeptide recognition motifs operate in a variety of phosphorylation-dependent and -independent biological processes, including the DNA damage response, signal transduction, and regulation of the cell cycle. More recently, two FHA domain-containing proteins were discovered in mammalian cells as tumor necrosis factor receptor-associated factor (TRAF)-interacting proteins: TIFA and TIFAB. TIFA and TIFAB are important and underappreciated modifiers of the innate immune signaling through their regulation of TRAF proteins. Recent studies have also revealed distinct roles for TIFA and TIFAB in the context of immune cell function, chronic inflammation, hematopoiesis, and hematologic disorders. Collectively, these studies indicate the important role of TIFA- and TIFAB-dependent signaling in hematopoietic cells and their dysregulation in several human diseases. In this review, we summarize the molecular mechanisms and biological role of these FHA-domain homologues, placing them into the context of human disease.