DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation

PP2C serine-threonine phosphatase, Wip1, is an important regulator of stress response. Wip1 controls a number of critical cellular functions: proliferation, cell cycle arrest, senescence and programmed cell death, apoptosis or autophagy. Ppm1d, the gene encoding Wip1 phosphatase, is expressed in hematopoietic progenitors, stem cells, neutrophils, macrophages B and T lymphocytes in bone marrow and peripheral blood. The Wip1 -/- mice display immunodeficiency, abnormal lymphoid histopathology in thymus and spleen, defects in B- and T-cell differentiation, as well as susceptibility to viral infection. At the same time, Wip1 knockout mice exhibit pro-inflammatory phenotype in skin and intestine in the model of inflammatory bowel disease (IBD) with elevated levels of inflammation-promoting cytokines TNF-alpha, IL-6, IL-12, IL-17. Several Wip1 downstream targets can mediate Wip1 effects on hematopoietic system including, p53, ATM, p38MAPK kinase, NFkB, mTOR. Here, we summarized the current knowledge on the role of Wip1 in the differentiation of various hematopoietic lineages and how Wip1 deficiency affects the functions of immune cells.