Abstract：
Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPP) belong to the protein phosphatase magnesium/manganese-dependent family of Ser/Thr phosphatases. Their general role as tumor suppressors has been documented for over a decade. In recent years, accumulating evidence suggests that PHLPP isozymes have key regulatory roles in both innate and adaptive immunity. In macrophages, PHLPP1 dampens signaling through TLR4 and the IFN-γ receptor by altering cytosolic signaling pathways. Additionally, nuclear-localized PHLPP1 inhibits STAT1-mediated inflammatory gene expression by direct dephosphorylation at Ser 727. PHLPP1 also regulates the migratory and inflammatory capacity of neutrophils in vivo. Furthermore, PHLPP1-mediated dephosphorylation of AKT on Ser 473 is required for both the suppressive function of regulatory T cells and for the pro-apoptotic effects of PHLPP1 in B cell chronic lymphocytic leukemia. In the context of immune homeostasis, PHLPP1 expression is modulated in multiple cell types by inflammatory signals, and the dynamics of its expression have varying effects on the pathogenesis of inflammatory bowel disease and septic shock. In this review, we summarize recent findings on the functions of PHLPP in inflammatory and regulatory signaling in the context of both innate and adaptive immunity.
摘要：
Pleckstrin同源域富含亮氨酸的重复蛋白磷酸酶（PHLPP）属于Ser/Thr磷酸酶的蛋白质磷酸酶镁/锰依赖性家族。它们作为肿瘤抑制因子的一般作用已经记录了十多年。近年来,越来越多的证据表明，PHLPP同工酶在先天和适应性免疫中都具有关键的调节作用。在巨噬细胞中，PHLPP1通过改变细胞溶质信号传导途径抑制通过TLR4和IFN-γ受体的信号传导。此外,核定位的PHLPP1通过在Ser727处直接去磷酸化抑制STAT1介导的炎症基因表达。PHLPP1还调节中性粒细胞在体内的迁移和炎症能力。此外，在Ser473上，PHLPP1介导的AKT去磷酸化是调节性T细胞的抑制功能和PHLPP1在B细胞慢性淋巴细胞白血病中的促凋亡作用所必需的。在免疫稳态的背景下，PHLPP1表达在多种细胞类型中受到炎症信号的调节，其表达动力学对炎症性肠病和脓毒性休克的发病机制有不同的影响。在这次审查中,我们总结了PHLPP在先天免疫和适应性免疫背景下的炎症和调节信号功能的最新发现。
