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

Cell Rep. 2020 Feb 25;30(8):2776-2790.e6. doi: 10.1016/j.celrep.2020.01.093.

Abstract

TRAF-interacting protein with a forkhead-associated domain B (TIFAB) is implicated in myeloid malignancies with deletion of chromosome 5q. Employing a combination of proteomic and genetic approaches, we find that TIFAB regulates ubiquitin-specific peptidase 15 (USP15) ubiquitin hydrolase activity. Expression of TIFAB in hematopoietic stem/progenitor cells (HSPCs) permits USP15 signaling to substrates, including MDM2 and KEAP1, and mitigates p53 expression. Consequently, TIFAB-deficient HSPCs exhibit compromised USP15 signaling and are sensitized to hematopoietic stress by derepression of p53. In MLL-AF9 leukemia, deletion of TIFAB increases p53 signaling and correspondingly decreases leukemic cell function and development of leukemia. Restoring USP15 expression partially rescues the function of TIFAB-deficient MLL-AF9 cells. Conversely, elevated TIFAB represses p53, increases leukemic progenitor function, and correlates with MLL gene expression programs in leukemia patients. Our studies uncover a function of TIFAB as an effector of USP15 activity and rheostat of p53 signaling in stressed and malignant HSPCs.

Keywords: AML; DUB; TIFA; TIFAB; TRAF6; USP15; hematopoiesis; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Line, Tumor
  • Disease Models, Animal
  • HEK293 Cells
  • Hematopoiesis*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Protein Binding
  • Signal Transduction*
  • Stress, Physiological
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Specific Proteases / chemistry
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination

Substances

  • Intracellular Signaling Peptides and Proteins
  • Tifab protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Myeloid-Lymphoid Leukemia Protein
  • USP15 protein, human
  • Ubiquitin-Specific Proteases