背景:具有PDZ结合基序(TAZ)的转录共激活因子在大多数组织中广泛表达,并与几种转录因子相互作用以调节细胞增殖,分化,和死亡,从而影响器官发育和大小控制。然而,人们对TAZ在免疫系统中的功能及其与炎症性皮肤病的关系知之甚少,因此,我们研究了TAZ在银屑病发病机制中的作用。
结果:有趣的是,TAZ在相关的肥大细胞中表达,特别是在溶酶体中,并与组胺释放因子(HRF)共定位。TAZ缺乏促进肥大细胞成熟并增加肥大细胞的HRF表达和分泌。TAZ缺乏症中HRF的上调不是由于转录增加,而是由于蛋白质稳定,和TAZ恢复到TAZ缺陷细胞减少HRF蛋白。有趣的是,咪喹莫特(IMQ)诱导的银屑病,其中HRF作为主要的促炎因子,在TAZKO小鼠中比在WT对照中更严重。通过IMQ处理,HRF表达和分泌增加,并且在用IMQ处理的TAZKO小鼠中更显著。
结论:因此,由于HRF表达在TAZKO小鼠中稳定,银屑病的发病机制进展更快,提示TAZ通过调节HRF蛋白的稳定性在预防银屑病中发挥重要作用。
BACKGROUND: Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis.
RESULTS: Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (
HRF). TAZ deficiency promoted mast cell maturation and increased
HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced
HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control.
HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ.
CONCLUSIONS: Thus, as
HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability.