TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

Abstract

Graphical Abstract Highlights d TIFAB binds the catalytic domain of USP15 and increases its rate of deubiquitination d TIFAB regulates USP15-dependent signaling in hematopoietic cells d Loss of TIFAB sensitizes HSPCs to p53-dependent stress d TIFAB is overexpressed and functionally relevant in MLLrearranged AML

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

“…To gain additional insight into the functional role of TIFAB in del(5q) MDS/AML, a proteomics screen was performed to identify TIFAB-binding proteins. Mass spectrometry analysis confirmed that TIFAB binds endogenous TRAF6 in a human del(5q) AML cell line, but these studies also revealed that TIFAB readily binds the ubiquitin-specific peptidase USP15 [18]. A series of biochemical assays and co-immunoprecipitation experiments confirmed that TIFAB binds USP15, and this appears to be partly dependent on the deubiquitinating (DUB) activity of USP15.…”

“…Amidst emerging fields uncovering the fascinating connections between immune cell function, chronic inflammation, and malignant conditions, TIFA and TIFAB demand further understanding. Given the fact that TIFA and TIFAB are potential therapeutic targets in AML [18,39], studies elucidating structural information on TIFA and TIFAB should be useful for the development of novel therapeutics against infectious diseases and possibly cancers. These small FHA domain-containing proteins are potent signal transducers with pleiotropic effects, many of which are yet to be discovered.…”

“…Given that TIFAB played an important role in hematopoiesis and is implicated in hematologic malignancies associated with del(5q), Niederkorn et al [18] used tandem-affinity purification and proteomic analysis to identify TIFAB-interacting proteins in del(5q) AML cells. They reported a TIFAB interactome in the del (5q) AML cell line (HL-60), which has helped to clarify key signaling networks affected by TIFAB.…”

“…On the basis of these observations, it was unclear how TIFAB-deficient HSPCs would respond to an environmental challenge. To answer this question, Niederkorn et al [18] subjected TIFAB-deficient HSPCs to a variety of stressors, both in vitro and in vivo, which mimicked conditions of DNA damage, viral infection, and chemotherapy. The deletion of TIFAB sensitized murine HSPCs to all of these cellular stressors, which significantly impaired hematopoietic progenitor function of TIFAB-deficient cells.…”

“…Although the deletion of TIFAB in murine BM cells had little effect on levels of USP15 itself, a substantial reduction in MDM2 and KEAP1 could be observed. Ultimately the impairment of MDM2 and KEAP1 unleashed the cellular stress response through p53 in TIFAB-deficient HSPCs, thus sensitizing them to multiple cytotoxic insults [18]. Given that TIFAB and USP15 are both highly expressed in hematopoietic cells, it is possible that their interaction represents a tissue-specific, finetuned regulatory mechanism during hematopoiesis.…”